Method for treating tension-type headache

ABSTRACT

NMDA receptor antagonists, especially mirtazapine, can be used to treat tension-type headaches.

[0001] This application is a nonprovisional claiming the benefit under35 USC §119(e) of provisional Serial No. 06/085,413, filed 14 May 1998.This application is also a continuation-in-part of PCT/DK97/00502, filed4 Nov. 1997, a PCT application designating the United States, which is anonprovisional claiming the benefit under 35 USC § 119(e) of provisionalSerial No. 06/030,292, filed 5 Nov. 1996. All of the above applicationsare hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to a method of treatment orprevention of tension-type headache in a human in need of suchtreatment. In particular, the invention relates to a method of treatmentof tension-type headache comprising the administration of an agent oragents effective for the prevention or reduction of centralsensitization

GENERAL BACKGROUND

[0003] Types of Clearly Defined Headache Disorders.

[0004] Previously, headache disorders were not clearly distinguished andit was widely believed that they formed part of a continuum and werestrongly related. In 1988, The International Headache Society, (IHS) viaits ad hoc committee on classification published a document entitledClassification and Diagnostic Criteria for Headache Disorders, CranialNeuralgias and Facial Pain (Classification and Diagnostic Criteria forHeadache Disorders, 1988). A new entity was here defined by name oftension-type headache. This entity was practically the same asconditions previously called tension headache, muscle contractionheadache, psycho-myogenic headache and idiopathic headache. The IHSclassification also defined a number of other specific headachediseases. Today it therefore gives no meaning to talk about headache ingeneral. It would be the same as to discuss bellyache and chest painwithout specifying its type and etiology. Due to the development indiagnostic accuracy research results obtained before 1988 have uncertainvalidity.

[0005] Tension-type headache was subdivided by the IHS ClassificationCommittee into an episodic form occurring less than half of all days anda chronic form occurring half of all days or more. Furthermore, both ofthese divisions were further subdivided into a form with disorder ofpericranial muscle and a form without such disorder. It is thus crucialthat research and patents specify which of the subforms are included.Before the entity of tension-type headache was created, it was widelybelieved that this kind of headache was caused by muscle ischemia, aconcept later disproven by the present inventors (Langemark et al.1990). The term tension-type headache was created in order to indicatethat experts disagreed with the notion of tension-type headache beingsimply a kind of muscle pain. In fact, the term idiopathic headache wassuggested There is only a moderate co-morbidity with neck pain and lowback pain in sufferers of tension-type headache. Furthermore,Electromyography (EMG)-measurements have failed to detect an increase ofmuscle contraction sufficient to cause pain on a purely mechanical basisin tension-type headache patients whereas central factors such asdepression and anxiety have been attributed a significant role. Finally,a genetic factor has recently been shown to be involved in tension-typeheadache (Østergaard et al. 1996). From the point of view of mechanismsand definition tension-type headache is thus a specific entity which mayor may not share mechanisms with muscle pain in the head and in otherparts of the body. The classification and diagnostic criteria fortension-type headache are shown in Tables I and II. TABLE IClassification of headache disorders, cranial neuralgias, and facialpain (Headache Classification Committee 1988).  1. Migraine  2.Tension-type headache  3. Cluster headache and chronic paroxysmalhemicrania  4. Miscellaneous headaches unassociated with structurallesion  5. Headache associated with head trauma  6. Headache associatedwith vascular disorders  7. Headache associated with non-vascularintra-cranial disorder  8. Headache associated with substances or theirwithdrawal  9. Headache associated with noncephalic infection 10.Headache associated with metabolic disorder 11. Headache or facial painassociated with disorder of cranium,    neck, eyes, nose, sinuses,teeth,    mouth or other facial or cranial structures 12. Cranialneuralgias, nerve trunk pain and deafferentation pain 13. Headache notclassifiable

[0006] TABLE II Diagnostic criteria for episodic and chronictension-type headache (Headache Classification Committee 1988) II.1.Episodic tension-type headache A. At least 10 previous headache episodesfulfilling criteria B-D listed below. Number of days with such headache<180/year (<15/month) B. Headache lasting from 30 minutes to 7 days C.At least 2 of the following pain characteristics: 1. Pressing/tighteningquality 2. Mild or moderate severity (may inhibit, but does not prohibit   activities) 3. Bilateral location 4. No aggravation by walking stairsor similar routine physical    activity D. Both of the following: 1. Nonausea or vomiting (anorexia may occur) 2. Photophobia and phonophobiaare absent, or one but not the    other is present E. At least one ofthe following: 1. History, physical and neurological examinations do notsuggest    one of the disorders listed in groups 5-11 2. History and/orphysical and/or neurological examinations do    suggest such disorders,but they are ruled out by    appropriate investigations 3. Suchdisorders are present, but tension-type headache does not    occur forthe first time in close temporal relation to the    disorder II.2.Chronic tension-type headache A. Average headache frequency 15days/month (180 days/year) for 6 months fulfilling criteria B-D listedbelow B. At least 2 of the following pain characteristics: 1.Pressing/tightening quality 2. Mild or moderate severity (may inhibit,but does not    prohibit activities) 3. Bilateral location 4. Noaggravation by walking stairs or similar routine physical    activity C.Both of the following: 1. No vomiting 2. No more than one of thefollowing:    Nausea, photophobia or phonophobia D. At least one of thefollowing: 1. History, physical and neurological examinations do notsuggest    one of the disorders listed in groups 5-11 2. History and/orphysical and/or neurological examinations do    suggest such disorders,but they are ruled out by    appropriate investigations 3. Suchdisorders are present, but tension-type headache does    not occur forthe first time in close temporal relation    to the disorder

[0007] Epidemiological studies done by the inventors have shown thatchronic tension-type headache affects three percent of the population atany given time, the lifetime prevalence being as high as six percent(Rasmussen et al. 1991). Severe episodic tension-type headache definedas persons having headache twice a week or more occurs in approximatelyten percent of the population. Thus, tension-type headache is a seriousproblem with significant socio-economic implications, involving enormousloss of workdays and quality of life.

[0008] Previous Findings in General Pain Physiology and PainPharmacology

[0009] The possible pathogenic mechanisms of tension-type headache havepreviously been studied and discussed by Langemark et al. (Langemark etal. 1987, 1988, 1989) and by the group of Jean Schoenen (Schoenen et al.1987, 1991a, b). The latter group have mainly focused onelectrophysiological recordings as electromyography, and the jaw openingreflex as reflected by the so-called exteroceptive silent period (ES2)(Schoenen et al. 1987). On the basis of shortened ES2 periods inpatients with chronic tension-type headache compared to healthy controlsa limbic dysfunction was suggested, but these results have later beendisproven by more systematic investigations (Bendtsen et al. 1996a,Lipchik et al 1996, Zwart and Sand, 1996). Schoenen and other groupshave also studied mechanical pain thresholds on the extremities as wellas in the cranial region and decreased mechanical pain thresholds inseverely affected patients with chronic tension-type headache werereported (Schoenen et al. 1991a, Langemark et al. 1989), whereaspatients with the episodic form of tension-type headache are reported tohave normal thresholds compared to healthy controls (Hatch et al. 1992,Goebel et al. 1992, Jensen et al. 1993b). These authors suggested thatcentral mechanisms may be involved in the chronic subform and that theperipheral mechanisms played a role in the episodic form, but providedno further clues or arguments about the underlying mechanisms. One morerecent congress presentation and two scientific papers by the presentinventors have focused on the sensory mechanisms in tension-typeheadache as decreased thresholds and tolerances were found in andoutside the head of patients with chronic tension-type headacheindicating a generally increased sensitivity to noxious and innocuousstimuli (Bendtsen et al. 1995b, 1996b and 1996c). Similarly a congressreport and a scientific paper present data from patients studied duringand outside a spontaneous tension-type headache episode (Jensen et al.1995a and 1995b). Muscle tenderness was increased during the headacheepisode, whereas mechanical pain thresholds remained unchanged and thethermal pain tolerance decreased. It bias concluded that a peripheralsensitization may be one of the primary sources of pain and that centralsensitization may contribute to and maintain the pain in chronictension-type headache. However, these data did not provide any furtherclues for more specific localizations of the sensitization, could notlead to a precise experimental model and finally did not lead toguidance for specific treatment of tension-type headache.

[0010] Peripheral Induction of Central Sensitization

[0011] One of the most exciting developments in pain research over thepast decades has been the recognition that the response generated by thesomatosensory system to a defined input is not fixed or static. Inparticular, the increased knowledge on central sensitization; i.e.increased excitability of neurons in the central nervous system, hasbeen a major breakthrough in the understanding of chronic pain. In 1983Woolf and colleagues (Woolf 1933) demonstrated for the first time that aprolonged noxious input from the periphery is capable of sensitizingspinal dorsal horn neurons. It has later been demonstrated that thecentral sensitization is induced by repetitive C-fibre, but notA-fibre., input (Yaksh and Malmberg 1994). In the sensitized state, alow-intensity stimulus can generate pain, the phenomenon of allodynia.The low-intensity stimulus is mediated via low-threshold afferents,A-b-fibres, which do not normally mediate pain, and it has beensuggested that the major cause of increased pain sensitivity in thechronic pain condition is an abnormal response to A-b-sensory input(Woolf and Doubell 1994). The original findings by Woolf and colleagueson spinal dorsal horn sensitization have later been confirmed bynumerous independent laboratories (Mense 1993), and a similarsensitization of trigeminal brainstem nociceptive neurons followingstimulation of craniofacial muscle afferents has been reported by Hu etal. (Hu et al. 1992). While central sensitization may be of relevance inmany different chronic pain conditions it is particular likely in musclepain, because input from muscle nociceptors is more effective ininducing, prolonged changes in the behavior of dorsal horn neurons thanis input from cutaneous nociceptors (Wall and Woolf 1984).

SUMMARY OF THE INVENTION

[0012] The inventors of the present invention have discovered that thecentral nervous system is sensitized in patients suffering fromincreased myofascial pain in connection with tension-type headachebecause of prolonged nociceptive input from myofascial tissues. Thepresent inventors were then able to devise, for the first time, aneffective treatment of tension-type headache, which comprisesinteracting with neuronal transmission connected with nociception so asto prevent or reduce central sensitization.

[0013] A better understanding of the principle of the invention can bederived from the detailed description of the scientific background inthe scientific section below.

[0014] Scientific Section

[0015] Previous Findings in General Pain Physiology and PainPharmacology and Previous Findings in Tension-Type Headache.

[0016] Pain physiology and pain pharmacology have mostly been elucidatedin animal studies. There are, however, no animal models with any provenvalidity in tension-type headache. Furthermore, these animalexperimental studies are done in anaesthetized animals while thesensation of pain by definition can only occur in awake beings. Most ofthe experiments are also of an acute nature stimulating for millisecondsand recording responses for seconds, minutes or hours and are thereforeof uncertain validity for chronic tension-type headache. Finally, onlyfew studies have been done on myofascial tissues projecting via thetrigeminal nerve while the huge body of knowledge otherwise availabledeals with mechanisms of the spinal cord. None of the experimentalanimal studies mention any form of headache, neither do they suggestthat the results of these studies may be utilized for the treatment oftension-type headache. However, after the crucial findings leading tothe present invention were made, it is clear that the implications ofthe findings in relation to general pain physiology can also'be utilizedin relation to tension-type headache.

[0017] With respect to medicinal treatment of tension-type headache, theprior art mentions a variety of substances. The substance Flupirtin(ethyl 2-amino-6-(4-fluorobenylamino)-3-pyridylcarbamate), which issuggested to work as an NMDA glutamate receptor antagonist (Schwartz etal. 1981), has been suggested for use in the treatment of chronic orepisodic tension-type headache, as disclosed in EP 0 659 410 A2, andaccording to Wörz et al., 1996, it has shown positive effects. However,in these documents the substance is described as a muscle relaxant, andthe mechanism by which it is proposed to exert its effect in thetreatment of various conditions, including tension-type headache, is bylowering muscle tension. Thus, as opposed to the present inventors, theprior art understands and explains tension-type headache as a conditiondirectly and primarily caused by muscle tension. WO 96/32386 concernsarylglycinamide derivatives which are antagonists of neurokinins, andthese compounds are broadly claimed for use in the treatment of a widevariety of conditions in which neurokinins are supposed to beimplicated. Tension-type headache is mentioned as such a condition, butthere is no indication of what the mechanism of neurokinin involvementmight be. For all the above-mentioned prior art documents, it can besaid that the concept of central sensitization in relation totension-type headache as introduced by the present inventors, is notdescribed or contemplated at all. Indeed, the prior art does not appearto be concerned with the underlying physiological mechanisms oftension-type headache, but seems to reflect presently held notions ofpain physiology in general.

[0018] In connection with the present invention, the term“arylglycinamide derivative as disclosed in WO 96/32386” means acompound as defined in any of claims 1-17 of WO 96/32386. As appearsfrom the claims herein, these arylglycinamide derivatives are excludedfrom the definitions of all aspects of the present invention. Theexcluded arylglycinamide derivatives of claims 1-17 of WO 96/32386 areall comprised by the definition given in claim 1 of WO 96/32386. Thus,whenever reference is made to an “arylglycinamide derivative asdisclosed in WO 96/32386”, this means an arylglycinamide derivativecovered by the definition of claim 1 of WO 96/32386, that is:

[0019] Arylglycinamide derivatives of the general formula I

[0020]  and their pharmaceutically acceptable salts, in which

[0021] Ar is unsubstituted or 1-5 times substituted phenyl, orunsubstituted or 1 or 2 times substituted naphtyl [the substituents ofphenyl and naphthyl independently of each other being halogen (F, Cl,Br, J), OH, (C₁-C₄)alkyl, O—(C₁-C₄)alkyl, CF₃, OCF₃ or NR⁹R¹⁰ (whereinR⁹ and R¹⁰ independently of each other are H, methyl or acetyl)], or Aris phenyl substituted with —OCH₂O— or —O(CH₂)₂O—;

[0022] R¹ and R² together with the N to which the are bound form a ringof the formula

[0023]  wherein p is 2 or 3,

[0024] X means oxygen, N(CH₂)_(n)R⁶ or CR⁷R⁸, wherein

[0025] n is 0, 1 or 2,

[0026] R⁶ is (C₃-C₇)cycloalkyl, phenyl or naphthyl each phenyloptionally being 1-3 times substituted with halogen (F, Cl, Br, n),(C₁-C₄)allyl, O—(C₁-C₄)alkyl, CF₃, OCF₃ or NR¹⁵R¹⁶ (wherein R¹⁵ and R¹⁶independently of each other are H, methyl or acetyl);

[0027] R⁷ and R⁸ have one of the following meanings

[0028] a) when R³ is unsubstituted or substituted phenyl, then R⁷ and R⁸are H,

[0029] b) when R₈ is H, —CONH₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃, CN,

[0030]  or —C(O)N((C₁-C₃)alkyl)₂,

[0031]  then R⁷ is phenyl, phenyl substituted with 1-3 substituents[wherein the substituents independently from each other are halogen (F,Cl, Br, J), (C₁-C₄)alkyl, O—(C₁-C₄)alkyl, CF₃ or OCF₃], piperidinyl.1-methylpiperidinyl,

[0032] or

[0033] c) R⁷ and R⁸ together form the moiety

[0034] R³ is H, (C₁-C₄)alkyl, unsubstituted or 1-3 times substitutedphenyl, wherein the substituents independently of each other arehalogen, (C₁-C₄)alkyl, O—(C₁-C₄)alkyl, CF₃, OCF₃ or NR¹⁷R¹⁸ (wherein R¹⁷and R¹⁸ independently of each other are H, methyl or acetyl);

[0035] R⁴ is phenyl(C₁-C₄)alkyl or naphthyl(C₁-C₄)alkyl, wherein phenylmay be substituted with 1-3 substituents: which substituentsindependently of each other are halogen (F, Cl, Br, J), (C₁-C₄)alkyl,O—(C₁-C₄)alkyl, CF₃, OCF₃ or NR¹⁹R²⁰ (wherein R¹⁹ and R²⁰ independentlyof each other are H, methyl or ethyl, and

[0036] R⁵ is H, (C₁-C₄)alkyl, (C₃-C₆)cycloalkyl, CH₂COOH, —CH₂C(O)NH₂,—OH or phenyl(C₁-C₄)alkyl.

[0037] Novel Experimental Evidence for Neuronal Sensitization inTension-Type Headache.

[0038] As discussed, previous studies in tension-type headache have ingeneral terms indicated that there may be sensitization of muscle andnociceptive afferents and also in a non-specific way have suggested somekind of central sensitization. Whether one or the other kind ofsensitization is the more important or whether indeed they both co-existhas not been clear. Recent series of experiments by the presentinventors have now clearly shown that tension-type headache is indeedmuch more complicated than previously anticipated; thus neither thephenomenon of peripheral sensitization nor that of unspecific centralsensitization does in isolation explain the condition. The studies ofthe present inventors have demonstrated that mechanical force due tocontraction of chewing muscles may induce peripheral sensitization inchewing muscles and that this peripheral sensitization is an importantfactor which may or may not induce headache (Jensen and Olesen 1996).Whether this happens depends on the response of the central nervoussystem. Further experiments have shown for the first time that aqualitatively altered pain perception related to sensitization of secondorder nociceptive neurons is chronically present in subjects withtension-type headache (Bendtsen et al. 1996c). This is believed to befar the most important abnormality in tension-type headache. Thirdly,recent studies by the present inventors have demonstrated that inaddition to sensitization of second order nociceptive neurons, there isalso a component of a more unspecific sensitization of pain pathways athigher levels of the central nervous system (Bendtsen et al. 1996b).While sensitization of second order neurons is believed to be segmental(located only in those segments of the spinal cord/trigeminal nucleuswhich receive afferents from myofascial tissues), the sensitization ofhigher centers is of a general nature and results in increased painsensitivity all over the body. It is anticipated that the sensitizationof supraspinal neurons is a consequence of the considerably increasednociceptive input to these neurons (Lamour et al. 1983) because of thesensitization at the level of the spinal dorsal horn/trigeminal nucleus.Thus, the generalized pain hypersensitivity reflects the sensitizationof second order neurons. Moreover, a recent study (Ashina et al. 1998a,Example 4 herein) by the inventors has demonstrated that the nitricoxide synthase (NOS) inhibitor, L-N⁰ methyl arginine hydrochloride(L-NMMA), is effective in the treatment of patients with chronictension-type headache. Since NOS inhibitors reduce spinal dorsal hornsensitization induced by continues painful input from the periphery (Maoet al. 1997) this study provides additional evidence for centralsensitization at the level of the spinal dorsal horn/trigeminal nucleusin patients with tension-type headache. Another recent study (Example 8herein) by the inventors has demonstrated that L-NMMA reduces musclehardness in patients with tension-type headache. Increased musclehardness is anticipated to reflect central sensitization, since it isknown that central sensitization may increase the drive to motor neuronsboth at the supraspinal and at the segmental level (Woolf 1983),resulting in increased muscle activity and thereby in increased musclehardness. This study, therefore, also points towards centralsensitization in tension-type headache. Finally, the present inventorshave recently demonstrated that experimental tooth clenching inducesincreased tenderness of masticatory muscles in patients withtension-type headache and that the increased tenderness precedes theinduced headache by several hours (Jensen and Olesen 1996), and that thecentral nervous system is sensitized only in patients with tenderpericranial muscles and not in patients without tender pericranialmuscles (Jensen et al. 1998). Together these studies demonstrate thatthe central nervous system is sensitized at the level of the spinaldorsal horn/trigeminal nucleus in patients with tension-type headachebecause of prolonged nociceptive input from myofascial tissues. On thebasis of the combined findings of thc inventors, a novel and rathercomplex model of the mechanisms of tension-type headache has beendeveloped, as depicted in FIG. 1. In the following the model isdescribed in details and its significant implications for devisingsuccessful future drug treatment of tension-type headache are discussed.

[0039] The model is illustrated in FIG. 1, in which the abbreviationshave the following meaning:

[0040] V: Trigeminal nerve,

[0041] C2, C3: Second and third cervical segment of the spinal cord,

[0042] PAG: Periaquaductal grey,

[0043] DRN: Dorsal raphe nuclei,

[0044] on-cells: cells in ventromedial medulla, which activate painpathways, for instance by reducing the threshold in the tail flick test.

[0045] C, Ad, Ab: Fibers of the C, Ad, and Ab type

[0046] Model for the Development of Tension-Type Headache InvolvingNeuronal Sensitization.

[0047] The main circuitry in FIG. 1 is the following:

[0048] Voluntary muscle activity is initiated by the supplementary motorarea. This activates the motor cortex which again activates the motornucleus of the trigeminal nerve and anterior horn cells of the C2 and C3segments of the spinal cord causing contraction of chewing and neckmuscles. Simultaneously with the activation of motor cortex, thesupplementary motor area also activates the antinociceptive system.Therefore normal muscle activity, even when vigorous, is not normallyperceived as painful. Another way of activating the motor pathways isvia the limbic system which is concerned with emotions. When this systemis activated, as in states of anxiety and stress it is envisaged thatthe motor cortex and the pain facilitatory system are activatedsimultaneously. Thus, emotionally induced involuntary muscle contractionusually induces myofascial tenderness and pain. Both voluntary andemotionally triggered muscle contraction via mechanical stress andperhaps neurogenic inflammation increase afferent input from myofascialtissues via C-fibers, A-d-fibers and A-b-fibers. C-fiber input isresponsible for slow pain and, when prolonged, causes the so-calledwind-up phenomenon in second order neurons located in the nucleus of thetrigeminal tract and in segments C2 and C3 of the dorsal horn of thespinal cord. Wind-up is associated with increased sensitivity of secondorder neurons and an increase of their receptive fields. Furthermore,input via A-b-fibers becomes painful which is called allodynia. Inputfrom the periphery in a state of wind-up causes a more intense pain thannormally. With repeated or chronic micro traumatic or inflammatoryreactions in myofascial tissues peripheral nociceptores, primarilyprojecting via C-fibers, become sensitized. Substances involved inperipheral sensitization include the potassium ion, bradykinin,histamine, ATP, neurotrophins and possibly other growth factors (Meyeret al., 1994).

[0049] Synaptic Mechanisms in the Spinal Dorsal Horn/Trigeminal NucleusInvolved in Central Sensitization

[0050] How does repetitive C-fibre input to the spinal dorsal hornresult in abnormal responses to normal Ab-fibre inputs, i.e. in centralsensitization? The most likely answer is that C-fibre releasedneurotransmitters increase the excitability of dorsal horn neurons sothat previously ineffective Ab-fibre inputs to nociceptive dorsal hornneurons become effective (Woolf and Thompson 1991). Severalneurotransmitters are knows to be involved in nociceptive transmissionfrom C-fibre afferents to second order neurons in the spinal dorsalhorn. These neurotransmitters can largely be divided into gases, intopeptides, which are chains of amino acids, or into excitatory orinhibitory amino acids, which are chemically single amino acids and intoexcitatory or inhibitory amines.

[0051] Gases

[0052] The freely diffusible gas nitric oxide (NO) is probably releasedfrom C-fibres and acts after binding to the enzyme guanylate cyclase inpostsynaptic neurons. However, even though NO is considered of majorimportance in central sensitization, its exact role as aneurotransmitter is not yet clarified (Meller and Gebhart 1993).

[0053] Neurokinins

[0054] Neurokinins are a fairly of related peptides, including substanceP, neurokinin A, neurokinin B and bradykinin which are known to bereleased from C-fibres. Currently there are three known subclasses ofreceptors for these peptides: neurokinin-1, (NK1) NK₂ and NK₃ receptors.

[0055] PACAP

[0056] PACAP is expressed in abundant amounts in dorsal horn neurons andis believed to play a significant role in pain transmission or themodulation of pain transmission.

[0057] Calcitonin Gene-Related Peptide (CGRP)

[0058] The exact role of this peptide in pain transmission is not knownbecause of lack of selective receptor antagonists. However, CGRPprobably protracts the breakdown of substance P in the synaptic cleft,thereby adding to the level of excitability of the spinal cord(Dickenson 1996).

[0059] Other Peptides

[0060] Several other peptides such as somatostatin, neuropeptide Y andgalanin may be important, but their exact role in central sensitizationis not yet known.

[0061] Excitatory Amino Acids

[0062] It now appears that the excitatory amino acid glutamate plays adominant role in the development of central sensitization. Glutamate isused by most neurons in the brain and spinal cord as their majorexcitatory transmitter. The actions of glutamate are mediated by 4different receptor classes: the N-methyl-D-aspartate (NMDA), thea-amino-3-hydroxy-5-methyl-4-isoxazolyl-propionic acid (AMPA), thekainate receptors, and the metabotropic receptors. Of these receptors,especially the NMDA receptors are considered to be of crucial importancein central sensitization (Coderre et al. 1993).

[0063] Adenosine

[0064] The central terminals of primary afferent fibres do expressadenosine receptors (Levine and Taiwo 1994). Via these receptors,adenosine can inhibit voltage-gated calcium channels via activation of aG-protein resulting in an inhibition of transmitter release from theprimary afferent neuron (Rang et al. 1994). Adenosine agonists may alsoact to inhibit the firing of wide-dynamic neurons, probably through anincrease in potassium conductance. Furthermore, adenosine has beenreported to block the release of glutamate (Yaksh and Malmberg 1994). Insupport of these findings intrathecal adenosine has been shown toincrease the nociceptive threshold (Yaksh and Malmberg 1994). Adenosinedoes also play a role in the peripheral tissues. In the primary afferentnociceptor adenosine acting at the A₁-receptor inhibit hyperalgesia,while adenosine acting at the A₂-receptor produces hyperalgesia viaelevation of intracellular cAMP (Levine and Taiwo 1994).

[0065] Gamma Amino Butyric Acid (GABA)

[0066] GABA is an important inhibitory transmitter in the centralnervous system, and it has been suggested that the encoding oflow-threshold mechanical stimuli as innocuous depends completely uponthe presence of a tonic activation of intrinsic glycine and/or GABAergicneurons (Yaksh and Malmberg 1994). Furthermore, it has been demonstratedthat the administration of GABA antagonists can produce allodynia (Woolf1994). GABA_(B) agonists may act to inhibit the firing of wide-dynamicneurons, probably through an increase in potassium conductance (Yakshand Malmberg 1994) and GABA may also reduce the amount of transmitterrelease from the central terminals of primary afferent fibres by openingof chloride channels (Rang et al. 1994).

[0067] 5-hydroxytryptamine (5-HT)

[0068] 5-HT is a very important transmitter in the modulation of pain.While 5-HT has both analgesic and algesic properties, it acts mainly asan inhibitory pain transmitter in the central nervous system (Roberts1992). Thus, when 5-HT is applied directly to the spinal cord, itproduces analgesia (Fields and Basbaum 1994). The antinociceptiveeffects of 5-HT are mediated via many different 5-HT receptor subtypes.Thus, it is known that both the 5-HT₁, 5-HT₂ and 5-HT₃ receptors areinvolved in antinociception (Fields and Basbaum 1994).

[0069] Norepinephrine (NE)

[0070] Like 5-HT, also norepinephrine (NE) plays an important role as anendogenous antinociceptive transmitter. In general, noradrenergiccontrols are mediated at the spinal level by the action at thea-2-adrenergic receptor (Fields and Basbaum 1994). The a-2-agonistclonidine has been shown to block the release of transmitters andpeptides in primary afferent terminals by presynaptic action, and it ismost likely that the analgesic effects of the tricyclic antidepressantspartly depend on their inhibition of norepinephrine re-uptake (Boivie1994).

[0071] Intracellular Mechanisms in the Spinal Dorsal Horn/TrigeminalNucleus Involved in Central Sensitization.

[0072] Why are the NMDA receptors considered so important? The actionsof many receptors on neuronal excitability are via opening or closing ofion channels. The ion channel for the NMDA receptors allows vast amountsof calcium into the neuron, so much that the resultant increase inexcitability exceeds that produced by all other receptors (Dickenson1996). The increase in intracellular calcium initiates a cascade ofbiochemical events. Thus, calcium activates a calmodulin-sensitive siteon NO synthase, which results in the production of NO. NO may thereafteract via at least three different mechanisms: 1) it may act in the neuronwhere it is produced, e.g. by increasing cyclic guanylate monophososphate (cGMP) levels which again will activate protein kinases orby inducing the expression of immediate early genes. The protein kinasesand the protein products of immediate early genes may then act as thirdmessengers and control the expression of other genes involved in thesynthesis of growth factors, channel proteins, peptides and enzymes; 2)it may act as a retrograde transmitter by diffusion to the presynapticneuron where it modulates excitability and enhances synapticconnections; and 3) it may diffuse to adjacent neurons, e.g.interneurons (Meller and Gebhart 1993). Another important result ofincreased intracellular calcium is the activation of phospholipase A₂,leading to increases in intracellular arachidonic acid and thesubsequent formation of cyclooxygenase and lipooxygenase products.Prostaglandins have been shown to increase calcium conductance on dorsalroot ganglion cells and to increase the secretion of primary afferentpeptides such as substance P (Yaksh and Malmberg 1994). Activation ofthe NMDA receptors thus has dramatic consequences and the receptors aretherefore usually blocked, such that they do not participate in normaltransmission. This channel block, which is mediated by physiologicallevels of Mg²⁺ ions, can only be removed by sufficient repeateddepolarization of the membrane. It is suspected that the neurokininsco-released with glutamate from C-fibres contribute to the removal ofMg²⁺ ions. This important action of the neurokinins is probably mediatedvia NK₁ and NK₂ receptors (Dickenson 1996). Also the protein kinasesactivated by NO will feed back on the NMDA receptors, causingphosphorylation and partial removal of the Mg²⁺ channel blockade (Woolf1996). Other glutamate receptors are probably also involved in centralsensitization, but the exact mechanisms are not yet known.

[0073] Altered Pain Perception after Central Sensitization

[0074] The increased excitability of neurons in the spinal dorsalhorn/trigeminal nucleus has dramatic consequences for the painperception in the individual patient. In the sensitized state, pain canbe generated by low-threshold Ab-fibres (allodynia) (Torebjörk et al.1992), the response to activation of high-threshold afferents isexaggerated (hyperalgesia) (Woolf 1994), and since the receptive fieldof the dorsal horn neuron is increased, the central sensitization willalso be manifest as a spread of hypersensitivity to uninjured sites(secondary hyperalgesia) (Torebjörk et al. 1992).

[0075] Central Sensitization in the Brain

[0076] When noxious input is received in the nucleus of the trigeminaltract, its further transmission to the thalamus and sensory cortexdepends on the intensity of the input and on the balance between paininhibiting and pain facilitating descending systems originating from thebrain stem. When the pain inhibiting system is activated, it decreasesthe likelihood that incoming stimuli are being transmitted to thethalamus and, alternatively, when the facilitatory system is activated,it increases the likelihood of this event. From the thalamus,nociception is projected further to the sensory cortex. Via unknownmechanisms pain causes a reflex increase in muscle tone. It is envisagedthat this response to pain is mediated via the limbic system becausepain and anxiety are closely interrelated. There is also a cross-talkbetween nociception and motor activity at the level of the trigeminalnucleus/spinal cord. Finally, pain activates the sympathetic systemcausing release of noradrenaline. This again is responsible for anincreased pain sensation, so-called sympathetically aggravated ormaintained pain.

[0077] Detailed Model for the Progression of Tension-Type Headache

[0078] The progression of episodic tension-type headache into chronictension-type headache often takes several years and happens only in aminority of episodic tension-type headache sufferers. A geneticdisposition (Østergaard et al. 1996) as well as several environmentalfactors seem to be involved in the development of chronicity. Despitethe fact that the progression is continuous, it is best illustrated by anumber of scenarios.

[0079] Scenario 1: Mild and moderate muscle contraction in normals.Voluntary muscle contraction in relation to normal functions such ascheating or head holding is initiated from the supplementary motorcortex. This is probably associated with only a minor increase innociception from myofascial tissues and no wind-up in non-headachesufferers. Simultaneously the antinociceptive system is activated suchthat no sensation of pain occurs.

[0080] Scenario 2: Forceful and/or long-lasting muscle activity innormals. With particularly vigorous muscle activity and especially whenit is very protracted, the strain on myofascial tissues may be such thatnociception is rather marked and tenderness and local pain may occur,but it is rapidly controlled by local reparative mechanisms inmyofascial tissues and a continuously active antinociceptive system.Tenderness without spontaneous pain on the day after exercise may be aresult of this balance or may be a purely local phenomenon.

[0081] Scenario 3: Involuntary muscle activity induced by the limbicsystem in normals: In contrast to activation initiated by thesupplementary motor area, muscle contraction initiated by the limbicsystem is not associated with an increased antinociceptive activity. Onthe contrary it is proposed to be associated with increased activity inthe pain facilitatory system. An alternative is a decrease in theactivity of the antinociceptive system, but this is unlikely becausethis system is normally not tonically active. Limbic initiated muscleactivity therefore causes pain even with moderate degrees of contractionand also with relatively short-lasting contractions. However, in normalsthe drive from the limbic system is short lasting and so are the mildchanges in myofascial tissues induced by the motor activity. Theheadache is therefore self limiting.

[0082] Scenario 4: Voluntary contraction in patients with severeepisodic—and chronic but not daily tension-type headache. In most ofthese individuals voluntary muscle activity will be painful. In partthis is due to permanent sensitization of second order neurons in thenucleus of the trigeminal tract, in part it is due to the fact (Jensenand Olesen 1996) that the antinociceptive system is not activated asnormally. Contraction therefore aggravates tenderness and causes painfrom the myofascial structures (Jensen and Olesen 1996) The process ofreverting the system back to normal may be more or less effective. Thisvariable duration of the initiating stimulus accounts for the variableduration of the headache.

[0083] Scenario 5: Severe (daily) chronic tension-type headache.

[0084] In severe chronic tension-type headache there is a state ofchronic sensitization in myofascial tissues and in central pain pathwaysboth at the second order neurons and at higher centers. There is a minorconstant elevation of EMG signal from cranial muscles. In addition, themost severe cases also have a more diffuse sensitization revealed indecreased pain thresholds throughout the body (Bendtsen et al. 1996b).Chronically increased muscle activity maintains a state of chronicperipheral sensitization which again maintains a state of chronicsensitization in the second order neurons in the nucleus of thetrigeminal tract (Bendtsen et al. 1996c). This causes steady inflow ofnociceptive signals to the thalamus and the perception of chronic painby the sensory cortex. This again activates the limbic system andstimulates tonic involuntary muscle activity. In this situation ofchronic pain there is probably also activation of the, sympatheticnervous system adding a component of sympathetically mediated pain tothe whole picture. On top of this chronic situation of sustained pain,it is easy to see how additional strain would result in increased andprolonged pain. A further increase in muscle activity would for instancein the sensitized peripheral myofascial tissues lead to a stronger thannormal nociceptive input to the already sensitized nucleus of thetrigeminal tract which would project to already sensitized hemisphericpain centers. A vicious circle has been set up and it may becomepermanent due to changes in gene transcription and consequent structuralchanges in neurons and synapses.

[0085] Rationale for the Novel Strategy According to the Invention forthe Treatment of Tension-Type Headache

[0086] Previous treatments have primarily been directed towards reducingmuscle contraction i.e. biofeedback treatment, physiotherapy, dentaltreatment, exercises and muscle relaxants. All of these treatments havehad limited or no success. It follows from the model according to thepresent inventors that therapeutic intervention should be directed,primarily towards the afferent system and above all againstsensitization of second order neurons in the nucleus of the trigeminaltract and upper cervical segments. Furthermore, it follows that whileintervention using peripherally acting analgesics or other measureswhich reduce peripheral nociceptive input is sufficient in episodictension-type headache, this is not so for severe episodic and chronictension-type headache, where sensitization of second order neuronsoccurs. In these patients, desensitization of these neurons should bethe major target for drug intervention. It may, however, be difficult todesensitize these neurons in face of an ongoing vigorous input from theperiphery. Therefore, drugs which reduce peripheral sensitization may beneeded in addition to the drugs which desensitize second ordernociceptive neurons, or drugs working at both levels may be needed.Preferably treatment should be given early enough to preventsensitization of second order neurons. Alternatively, if markedsensitization at the cortical level occurs, the individual beinghypersensitive to painful stimuli all over the body, it may not beenough to intervene against the sensitization of second order neurons.For such patients intervention against cortical sensitization isrecommended as an additional measure.

[0087] The Novel Therapeutic Principle According to the Invention forTreatment of Tension-Type Headache

[0088] According to the present invention, several means of interveningagainst tension-tape headache can be envisaged, depending on the levelaccording to the above, at which the intervention is aimed. In eithercase, be it in the periphery, the second order neurons of the sensorytrigeminal nucleus or the cortex, the intervention must target thetransmission of nerve impulses. A number of different transmittersubstances are involved in this transmission at each level. Thus, theinvention, in some of its aspects, relate to the following therapeuticprinciples in tension-type headache of the chronic type and of thesevere episodic type defined as having headaches ten or more days permonth:

[0089] Administration of agents or drugs (in the present specificationand claims, the terms agent and drug are used as interchangeable) whichprevent or reduce sensitization of second order nociceptive neuronslocated in the nucleus of the descending tract of the trigeminal nerveand in the C2 and C3 segments of the dorsal cervical horn of the spinalcord. There are several known types of assays indicating the capabilityof an agent to prevent or reduce central sensitization. In thefollowing, 13 such assays are described.

[0090] Administration of agents or drugs which reduce supraspinal painsensitization to a normal level. These are agents or drugs whichnormalize the response of pressure pain thresholds in the temporalregion to tooth clenching and drugs which normalize pain thresholds inhand.

[0091] Administration of agents or drugs which reduce peripheralsensitization defined as agents or drugs which prevent the developmentof abnormal tenderness due to tooth clenching.

[0092] Administration of agents or drugs which normalize the painresponse to intra muscular infusion of bradykinin, 5-HT, histamine,prostaglandines and/or nitroglycerine.

[0093] Administration of agents or drugs which normalize local pressurepain threshold over myofascial tissues of the head.

[0094] Administration of agents or drugs which have more than one of theabove effects.

[0095] Administration of agents or drums which in a panel of testpatients with tension-type headache have one of the above effectsdescribed one by one.

[0096] When targeting the transmission of nerve impulses according tothe invented model, it is preferred to interact with the followingsubstances relating to neurotransmission in connection with pain:

[0097] Glutamate

[0098] Substance P

[0099] Nitric oxide

[0100] GABA

[0101] It is particularly preferred to:

[0102] Antagonize the effect of glutamic acid

[0103] Antagonize the effect of substance P

[0104] Antagonize the effect of nitric oxide

[0105] Stimulate the effect of GABA.

[0106] More specifically, it is preferred to use:

[0107] NMDA receptor antagonists

[0108] Inhibitors of neuronal nitric oxide synthase (NOS)

[0109] GABA A and GABA B receptor agonists

[0110] Counteraction of Central Sensitization of Second Order Neurons

[0111] In order to counteract central sensitization of second orderneurons of the sensory trigeminal nucleus/dorsal horn, it will beadvantageous to cause a decrease in neuronal transmission involving thepathways utilizing e.g. the transmitter substances glutamate, nitricoxide, and the neurokinins (substance P, bradykinin, neurokinin A,neurokinin B). Also, it will be of interest to counteract the action ofsecond messengers such as guanylate cyclase, cGMP as well as any furthersteps in the action of cGMP in second order sensory neurons receivingnociceptive input from the head and neck.

[0112] Prevention of Central Sensitization of Second Order Neurons

[0113] In order to prevent the occurrence of central sensitization ofsecond order neurons of the sensory trigeminal nucleus/dorsal horn, itwill be advantageous to normalize neuronal transmission in theperipheral and/or central nervous system involving transmittersubstances such as glutamate, GABA, adenosine, nitric oxide, theneurokinins (substance P, bradykinin, neurokinin A, neurokinin B),neurotrophins and histamine. While it might have seemed advantageous touse 5-HT_(1D) receptor agonists because they stabilize presynapticnociceptive terminals, studies by the inventors have shown that acompound of this class (sumatriptan) is not effective to a clinicallyrelevant extent in tension-type headache although it is highly effectivein migraine (Brennum et al. 1992, 1996). Counteracting excitatory 5-HTreceptors, such as 5-HT₂ and 5-HT₃ localized on second order neurons,however, are contemplated to be effective in the treatment oftension-type headache in accordance with the present invention

DETAILED DESCRIPTION OF TEE INVENTION

[0114] On the basis of their experimental discoveries and analyses, thepresent inventors have devised, for the first time, a strategy for thetreatment or prevention of tension type headache. Up to now, there hasnot been any effective treatment available for tension type headache,which has been a very serious problem in view of the very highprevalence of tension-type headache.

[0115] The present invention relates to a method of treatment orprevention of tension-type headache in a person in need of suchtreatment, the method comprising administering an amount of an agenteffective to interact with neuronal transmission connected with painperception so as to prevent or reduce central sensitization.

[0116] The attainment of prevention or reduction of centralsensitization can be demonstrated by one of the following assays:

[0117] 1) Normalization of a pathological qualitatively alteredstimulus-response function. The attainment of a normalization of aqualitatively altered stimulus-response function in connection withnociception (Bendtsen et al. 1996c, Example 1) can be demonstrated bypalpation of the trapezius muscle and recording of the degree of paincorresponding to the intensity of palpation (Bendtsen et al. 1994). Whena curve representing the stimulus/response function in connection withnociception has changed in shape from being substantially linear in anormal representation to being substantially linear in a doublelogarithmic representation, a normalization of the qualitatively alteredstimulus/response function has been obtained. In the present context, anagent which normalizes a qualitatively altered stimulus-responsefunction in connection with nociception is an agent which, whenadministered to a group of at least 20 patients suffering fromtension-type headache, will cause the curve representing thestimulus/response function ion in connection with nociception to becomesubstantially linear when represented double logarithmically in at least10 of the patients. Preferably, the agent so defined has such an effectin at least 12 of the patients. More preferably, the agent so definedhas such an effect in at least 14 of the patients.

[0118] 2) Normalization of a pathological abnormally low pain threshold.Th attainment of a normalization of an abnormally low pain threshold canbe demonstrated by the measurement of the pressure pain threshold in theextremities or in the pericranial region with an electronic pressurealgometer or by the measurement of the electrical pain threshold with aconstant current stimulator as previously described (Bendtsen et al.1996a). When the pain threshold has changed from being significantlylower in a group of patients with tension-type headache than in a groupof healthy controls to be not significantly different between the twogroups, a normalization of the abnormally low pain threshold has beenobtained. In the present context, an agent which normalizes anabnormally low pain threshold is an agent which, when administered to agroup of at least 10 patients suffering from tension-type headache, willchange the pain threshold from being significantly lower than that in agroup of healthy controls to be not significantly different between thetwo groups.

[0119] 3) Reduction of a pathological pericranial muscle hardness. Theattainment of reduction of pericranial muscle hardness can bedemonstrated by the measurement of hardness in the pericranial muscleswith a hardness meter as previously described (Ashina et al. 1998a).When the muscle hardness is reduced significantly more following theadministration of a given agent than following the administration ofplacebo, a reduction of muscle hardness has been obtained. In thepresent context, an agent which reduces pericranial muscle hardness isan agent which, when administered to a group of at least 10 patientssuffering from tension-type headache, will reduce pericranial musclehardness significantly more than placebo. Such a reduction willtypically be at least 10%. Preferably the reduction will be at least20%. More preferably the reduction will be at least 30%.

[0120] 4) Reduction of a pathological increased pericranial myofascialtenderness. The attainment of reduction of increased pericranialmyofascial tenderness can be demonstrated by the measurement of thetenderness in the pericranial region using the Total Tenderness Scoringsystem as previously described (Bendtsen et al. 1995). Myofascialtenderness is considered to be increased when the Total Tenderness Scoreor the Local Tenderness Score in the pericranial region is above the 75%percentile of the Total Tenderness Score or the Local Tenderness Scorein a group of healthy controls (Jensen and Rasmussen 1996). In thepresent context, an agent which reduces increased pericranial myofascialtenderness is an agent which, when administered to a group of at least10 patients suffering from tension-type headache, will reduce the TotalTenderness Score or the Local Tenderness Score in the pericranial regionby at least 10% compared with the administration of placebo. Preferably,the agent so defined will reduce the Total Tenderness Score or the LocalTenderness Score in the pericranial region by at least 20% compared withthe administration of placebo. More preferably, the agent so definedwill reduce the Total Tenderness Score or the Local Tenderness Score inthe pericranial region by at least 30% compared with the administrationof placebo.

[0121] 5) Prevention or reduction of pain, tenderness or hardness inpericranial muscles, or prevention or normalization of a qualitativelyaltered stimulus-response function or a reduced pain threshold inducedby experimental tonic muscle contraction. The attainment of preventionor reduction of pain, tenderness or hardness, or prevention ornormalization of a qualitatively altered stimulus-response function or areduced pain threshold can be demonstrated as described in assays 1-4above. Experimental tonic muscle contraction can be obtained byclenching of the molar teeth for 30 minutes at 10% of the individualsubject's maximal voluntary contraction measured from electromyographicrecordings of the activity in the temporal or masseter muscles aspreviously described (Jensen and Olesen 1996). In the present context,an agent which prevents or reduces pain, tenderness or hardness, orprevents or normalizes a qualitatively altered stimulus-responsefunction or a reduced pain threshold induced by experimental tonicmuscle contraction is an agent which, when administered to a group of atleast 10 human subjects, will prevent or reduce pain, tenderness orhardness, or prevent or normalize a qualitatively alteredstimulus-response function or a reduced pain threshold induced byexperimental tonic muscle contraction to a significantly higher degreethan placebo.

[0122] 6) Prevention or reduction of pain, tenderness or hardness inpericranial muscle, or prevention or normalization of a qualitativelyaltered stimulus-response function or a reduced pain threshold inducedby intra muscular infusion of algogenic substances. The attainment ofprevention or reduction of pain, tenderness or hardness, or preventionor normalization of a qualitatively altered stimulus-response functionor a reduced pain threshold can be demonstrated as described in assays1-4 above. Intra muscular infusion of algogenic substances can beperformed by the use of a 0.4 mm needle as previously described (Jensenet al. 1990). Algogenic substances such as bradykinin, serotonin,histamine, adenosine-tri-phosphate, prostaglandines, capsaicin,hypertonic saline, potassium, nitroglycerine or combinations hereof canbe used. The algogenic substances can be injected either as a singlebolus injection (Jensen et al. 1990) or as a prolonged infusion (Zhanget al. 1993). In the present context, an agent which prevents or reducespain, tenderness or hardness, or prevents or normalizes a qualitativelyaltered stimulus-response function or a reduced pain threshold inducedby intra muscular infusion of algogenic substances is an agent which,when administered to a group of at least 10 human subjects, will preventor reduce pain, tenderness or hardness, or prevent or normalize aqualitatively altered stimulus-response function or a reduced painthreshold induced by intra muscular infusion of algogenic substances toa significantly higher degree than placebo.

[0123] 7) Prevention or reduction of pain, tenderness or hardness inpericranial muscle, or prevention or normalization of a qualitativelyaltered stimulus-response function or a reduced pain threshold inducedby stimulation of nociceptive afferents in myofascial tissues. Theattainment of prevention or reduction of pain, tenderness or hardness,or prevention or normalization of a qualitatively alteredstimulus-response function or a reduced pain threshold can bedemonstrated as described in assays 1-4 above. Stimulation ofnociceptive afferents in myofascial tissues can be obtained by methodssuch as eccentric muscle contraction (Howell et al. 1993), prolongedstatic muscle contraction, repeated monotonous muscle work, ischemicmuscle exercise (Myers and McCall Jr 1983), electrical stimulation vianeedle electrodes inserted into the muscles (Vecchiet et al. 1988) ormechanical pressure applied to the muscles. In the present context, asubstance which prevents or reduces pain, tenderness or hardness, orprevents or normalizes a qualitatively altered stimulus-responsefunction or a reduced pain threshold induced by stimulation ofnociceptive afferents in myofascial tissues is a substance which, whenadministered to a group of at least 10 human subjects, oil prevent orreduce pain, tenderness or hardness, or prevent or normalize aqualitatively altered stimulus-response function or a reduced painthreshold induced by stimulation of nociceptive afferents in myofascialtissues to a significantly higher degree than placebo.

[0124] 8) Prevention or reduction of secondary allodynia or secondaryhyperalgesia induced by stimulation of nociceptive afferents inmyofascial tissues. The attainment of prevention or reduction ofsecondary allodynia or secondary hyperalgesia can be demonstrated bymeasuring pain sensitivity in the unaffected tissue area that surroundsan area in which nociceptive afferents are stimulated (Magerl et al.1998). Pain sensitivity can be measured by visual analogue scalerecording of the pain intensity evoked by stimuli such as mechanicalpressures applied by an electronic pressure algometer, manual palpationor pressure-controlled palpation (Bendtsen et al. 1995; Bendtsen et al.1996a), punctuate mechanical stimuli applied by von Frey hairs (Magerlet al. 1998), light touch stimuli applied by a soft cotton wisp (Magerlet al. 1998), thermal stimuli applied by the Marstock thermotest(Norregaard et al. 1997) or electrical stimuli applied by surfaceelectrodes (Bendtsen et al. 1996a) or intra muscular needle electrodes(Vecchiet et al. 1988) or by measuring the nociceptive flexion reflex(Willer et al. 1984). Stimulation of nociceptive afferents in myofascialtissues can be obtained as described in assays 5-7 above. In the presentcontext, an agent which prevents or reduces secondary allodynia orsecondary hyperalgesia induced by stimulation of nociceptive afferentsin myofascial tissues is an agent which, when administered to a group ofat least 10 human subjects, will prevent or reduce secondary allodyniaor secondary hyperalgesia induced by stimulation of nociceptiveafferents in myofascial tissues to a significantly higher degree thanplacebo.

[0125] 9) Prevention or reduction of wind-tip induced by repetitivestimulation of nociceptive afferents in the pericranial region. Theattainment of prevention or reduction of wind-up can be demonstrated bymeasuring pain sensitivity to repeated stimuli (Magerl et al. 1998),since temporal summation of painful stimuli is regarded as apsychophysical correlate of wind-up (Price et al. 1994). In the presentcontext, wind-up is defined to be present when repeated identicalstimuli become increasingly painful (Pedersen et al. 1998). Wind-up canbe induced by stimuli such as repeated electrical stimuli, e.g. fivestimuli of 1 ms duration with an intensity of 1.4 times the baselinepain threshold delivered at 2 Hz by a constant current stimulator(Pedersen et al. 1998), or as repeated punctuate mechanical stimuli,e.g. five stimuli delivered at 2 Hz with a 256 mN calibrated von Freyhair (Magerl et al. 1998). The evoked pain intensity can be measuredusing a visual analogue scale. In the present context, an agent whichprevents or reduces wind-up induced by stimulation of nociceptiveafferents in the pericranial region is an agent which, when administeredto a group of at least 10 human subjects, will prevent or reduce wind-upinduced by stimulation of nociceptive afferents in the pericranialregion to a significantly higher degree than placebo.

[0126] 10) Prevention or reduction of secondary allodynia or secondaryhyperalgesia induced by nociceptive input in an experimental animalmodel. The degree of secondary allodynia or secondary hyperalgesia canbe examined by measuring pain sensitivity in the unaffected tissue areathat surrounds an area in which nociceptive afferents are stimulated(Magerl et al. 1998). Pain sensitivity can be measured by recording theresponse of the animal to well-defined stimuli, e.g. briskly strokingthe skin Faith the blunt point of a pencil (Magerl et al. 1998),mechanical pressures applied by an electronic pressure algometer, manualpalpation, pressure-controlled palpation or calibrated von Frey hairs(Hao et al. 1992), electrical stimuli or thermal stimuli (Hao et al.1992). The response of the animal can be measured by methods such as: a)grading of the behavior of the animal to avoid a given stimulus, e.g. asa score of 0: no response; 1: moderate efforts to avoid the stimulus;and 2: vigorous efforts to escape the stimulus (Hao et al. 1992); b)recording the time required for eliciting a given response of theanimal, e.g. withdrawal of an extremity, by a given stimulus (Hao et al.1992); c) recording the intensity of a stimulus that elicits a givenreaction, e.g. vocalization or withdrawal or licking of an extremity(Hao et al. 1992); or d) by a combination of the above-mentioned methods(Hao et al. 1992). The induction of secondary allodynia or secondaryhyperalgesia can be performed as described above in assays 6 and 7 or bymethods such as the application to the skin of chemical irritants, e.g.mustard oil (Woolf and King 1990), thermal stimuli (Hylden et al. 1989),pinching, subcutaneous or intra muscular injections of complete Freund'sadjuvant (Hylden et al. 1989). In the present context, an agent whichprevents or reduces secondary allodynia or secondary hyperalgesiainduced by nociceptive input in an experimental animal model is an agentwhich will prevent or reduce secondary allodynia or secondaryhyperalgesia induced by nociceptive input in an experimental animalmodel to a significantly higher degree than placebo.

[0127] 11) Prevention or reduction of wind-up induced by repetitivestimulation of nociceptive afferents in an experimental animal model.The degree of wind-up can be examined by measuring pain sensitivity(Magerl et al. 1998) or the activity of second order neurons to repeatedstimuli (Woolf and Thompson 1991). In the present context, wind-up isdefined to be present when repeated identical stimuli becomeincreasingly painful (Pedersen et al. 1998) or potentiate the responsesof second order neurons (Laird et al. 1995). Pain sensitivity in animalscan be recorded as described above in assay 10, while the activity ofsecond order neurons can be measured using extra- and intracellularrecordings of the activity, in these neurons (Woolf and King 1990; Hu etal. 1992). After exposure of the spinal cord via laminectomy,extracellular recordings can be made using glass microelectrodes andintracellular recordings can be made using potassium acetate electrodes(Woolf and King 1990). Wind-up can be induced by stimuli such as thosedescribed in assay 10. In the present context, an agent which preventsor reduces wind-up induced by repetitive stimulation of nociceptiveafferents in an experimental animal model is an agent which will preventor reduce wind-up induced by repetitive stimulation of nociceptiveafferents in an experimental animal model to a significantly higherdegree than placebo.

[0128] 12) Prevention or reduction of increased receptive field size ofsecond order neurons induced by nociceptive input in an experimentalanimal model. The receptive field size of second order neurons can bemeasured using extra- and intracellular recordings of the activity inthese neurons (Woolf and King 1990; Hu et al. 1992) as described abovein assay 11. The receptive fields can be mapped using stimulation with,e.g., calibrated von Frey hairs, blunt probes (Hylden et al. 1989),thermal stimuli (Hylden et al. 1989), serrated forceps or calibratedpinchers applied to the skin (Woolf and King 1990). The induction ofincreased receptive field size of second order neurons can be performedas described above in assay 10. In the present context, an agent whichprevents or reduces increased receptive field size of second orderneurons induced by nociceptive input in an experimental animal model isan agent which will prevent or reduce increased receptive field size ofsecond order neurons induced by nociceptive input in an experimentalanimal model to a significantly higher degree than placebo.

[0129] 13) Prevention or reduction of increased excitability of theflexion reflex induced by nociceptive input in an experimental animalmodel. The excitability of the flexion reflex can be examined bymeasuring the activity in flexor motor neurons elicited by a standardstimulus applied ipsilaterally to the recording of flexor motor neuronactivity (Woolf 1983). The examination can, e.g., be performed byextracellular recordings of the activity from flexor alpha motor neuronsto the posterior biceps femoris/semitendinosus muscles in thedecerebrate rat (Woolf and Thompson 1991). The flexion reflex can, e.g.,be elicited by a standard pinch applied to the ipsilateral toes (Woolfand Thompson 1991). The induction of increased excitability of theflexion reflex can be performed as described above in assay 10. In thepresent context, an agent which prevents or reduces increasedexcitability of the flexion reflex induced by nociceptive input in anexperimental animal model is an agent which will prevent or reduceincreased excitability of the flexion reflex induced by nociceptiveinput in an experimental animal model to a significantly higher degreethan placebo.

[0130] Prevention or reduction of central sensitization induced bynociceptive input in an experimental animal model. The degree of centralsensitization in an experimental animal model can be measured by othermethods which are presumed to reflect central sensitization but whichare not mentioned in the above described assays 10-13, i.e. measurementof cellular intermediate early genes such as c-fos (Dubner and Ruda1992). The induction of central sensitization can be performed asdescribed above in assay 10. In the present context, an agent whichprevents or reduces central sensitization induced by nociceptive inputin an experimental animal model is an agent which sill prevent or reducecentral sensitization induced by nociceptive input in an experimentalanimal model to a significantly higher degree than placebo.

[0131] In the present context the term “significantly higher degree thanplacebo” should be taken to mean statistically significant when therelevant statistical tests are applied to data relating to an effect ofan agent according to the invention compared to an effect of placebo inany given assay or test.

[0132] The interaction with neuronal transmission connected with painperception will normally be interaction with neuronal transmissionconnected with second order nociceptive neurons. This interaction willnormally involve prevention of sensitization by way of a reduction ofC-fiber input to the second order nociceptive neurons or reversal of analready established sensitization of second order nociceptive neurons.

[0133] Interaction with neuronal transmission connected with painperception can be exerted by increasing inhibitory synaptic stimuli orit can be exerted by decreasing excitatory synaptic stimuli.

[0134] By the term “palpation” is meant the act of applying, with thefingers, pressure to the surface of the body for the purpose ofdetermining the amount of pain elicited in the underlying tissue by saidpressure intensity.

[0135] In the present context, the term “qualitatively alteredstimulus/response function” in connection with nociception means thatthe function describing the amount of pain elicited by a given pressureintensity, sensed by a person being palpated, has changed in shape frombeing positively accelerating to being substantially linear, of Example1.

[0136] By the term “tender muscle” is meant a muscle in which pain iselicited by palpation with a clinically relevant pressure.

[0137] In the present context, by the term “central sensitization” ismeant that second order nociceptive neurons residing in the centralnervous system are rendered more sensitive than normally to incomingsynaptic stimuli. At the occurrence of central sensitization suchstimuli will elicit excitation of the said central neurons atstimulation below the normal threshold for excitation; thus, centralneurons possess an increased excitability.

[0138] In the present context, myofascial pain relates to pain in themyofascial tissue, by which is meant muscular structures, tendons andtendon insertions related to the pericranial and cervical region.

[0139] In the context of the present invention second order nociceptiveneurons are neurons located in the nucleus of the trigeminal tract andof C2 and C3 segments of medullary dorsal horns, said neurons beinginvolved in the processing of nociceptive stimuli.

[0140] By the term “C-fibers” is meant a class unmyelinated nociceptivefibers terminating on neurons in the nucleus of the trigeminaltract/dorsal horn of the spinal cord.

[0141] The interaction with neuronal transmission connected with painperception, so as to obtain a substantial prevention or a substantialnormalization of an otherwise qualitatively altered stimulus-responsefunction in connection with nociception is preferably performed byadministering an effective amount of an agent which prevents ornormalizes an otherwise qualitatively altered stimulus-response functionin connection with nociception.

[0142] In the present context, an agent which prevents or normalizes anotherwise qualitatively altered stimulus-response function in connectionwith nociception is an agent which, when administered to a group of atleast 20 patients suffering from tension tape headache as defined above,will cause the curve representing the stimulus/response function inconnection with nociception to become substantially linear whenrepresented double logarithmically in at least 10 of the patients.Preferably the agent so defined has such an effect in at least 12 of thepatients. More preferably the agent so defined has such an effect in atleast 14 of the patients.

[0143] A number of substances and classes of substances which interactsmith neuronal transmission to exert this function are know, confer thedetailed discussion thereof in the following.

[0144] In accordance with what is explained above, another way ofexpressing the treatment according to the invention is by reference topain threshold in connection with chronic contraction of muscle, inparticular tooth clenching. Thus, according to this, the invention canbe expressed as a method for treatment of tension-type headache in aperson in need of such treatment, comprising interacting with neuronaltransmission connected with pain perception so as to obtain asubstantial increase of an otherwise unresponsive pain threshold inconnection with chronic contraction of muscle, in particular toothclenching.

[0145] Again, the interaction is preferably performed by administeringan agent which will interact with neuronal transmission in a mannercorresponding to what has been described above. The agent can becharacterized as a agent which performs positively (as described above),in one or more of the assays described above, such as thestimulus/response function test described above, or as a agent which, ina group of at least 20 patients suffering from tension type headache asdefined above, will cause the effect of tooth clenching to be anincreased pain threshold instead of an abnormally low pain threshold inat least 10 of the patients, preferably at least 12 of the patients,more preferably in at least 14 of the patients.

[0146] In another aspect, the invention relates to an agent having theproperties defined herein for use as a medicament, in particular for thetreatment of tension-type headache. This aspect relates to thosesubstances or substance classes discussed herein which have notpreviously been used as medicaments or diagnostics. In a further aspect,the invention relates to the use of an agent having the propertiesdescribed herein for the preparation of a pharmaceutical composition forthe treatment or prevention of tension-type headache.

[0147] In one aspect of the present invention the treatment orprevention of tension-type headache according to the invention is notaccompanied by a substantial reduction of muscle tension.

[0148] In an important aspect the present invention relates to a methodfor treating tension-type headache in a person which comprisesadministering an agent in an amount effective to alleviate saidheadache, said agent being an agent capable of altering the relationshipof pain intensity to pressure intensity when the trapezoid muscle ispalpated at different pressure intensities in said person. Therelationship is typically substantially linear in the untreated persons,and substantially non-linear in the treated persons. Furthermore, therelationship will typically be positively accelerating in the treatedperson. In one embodiment of the present invention the rate ofacceleration of pain intensity with pressure intensity is substantiallyconstant. In one important embodiment of the present invention therelationship in the treated persons is substantially the same as incontrol persons who did not have tension-type headache and who weretreated with a placebo.

[0149] The agent interacting with neuronal transmission to substantiallynormalize an otherwise qualitatively altered stimulus/response functionin connection with nociception is preferably one which directlyquantitatively lowers pain perception, in that, in a panel of testpersons suffering from increased myofascial tenderness with disorder ofpericranial muscle in connection with tension-type headache, theadministration of the agent will result in transformation of asubstantially linear pain intensity perception in response to pressureintensity in trapezius as well as other relevant pericranial musclesinto a curve (C) of which the values of pain intensity are lower thanthe linear pain intensity perception.

[0150] The curve (C) is preferably a curve which can be describedsubstantially as a power function and is a curve which is substantiallylinear in a double logarithmic plot.

[0151] It is preferred that substantially each of the values of curve(C) is at the most 20% higher, preferably at the most 10% higher, thanthe value of the corresponding curve produced for a test panel ofhealthy controls.

[0152] In connection with any of the patient panel tests discussed aboveit is noted that the treatment with the agent in question should beperformed by administration at least once daily to maintain atherapeutic plasma level in the patients and should be continued for asufficient time to allow the agent to exert its therapeutic effect, butthat an agent is considered not to perform according to the particulartest if the effect is not obtained within a treatment time of threemonths. This does not mean that it will necessarily take three monthsfor an agent to exert its therapeutic effect; some compounds will showtheir therapeutic effect after much shorter treatment periods, down todays or even hours. In connection with testing of a new candidate agent,the dosage of the agent will normally be kept as high as permitted bythe toxicity of the compound during initial tests and %% ill then bereduced to a lower level which is still maximally effective during thetest proper.

[0153] Evaluation of the ability of an agent to provide an effectivetreatment for tension-type headache, by interacting with neuronaltransmission according to the present invention, may also be performedas an acute test, in which the agent is administered, typically as abolus or an infusion, to a group of patients suffering from chronictension-type headache. In such a test, the pain connected totension-type headache in these patients will typically be scored by thepatients, as described in example 4, at various time points afteradministration of the agent, typically at least every 15 min andsubsequently monitored over a period of at least 30 nun, typically atleast 60 min, preferably at least 90, more preferably at least 120 min.For the evaluation of a candidate agent, an additional group of patientsacutely suffering from tension-type headache will receive placebo andserve as a control group. The curves based on the pain scores ofpatients in both groups will typically be compared, as shown in FIG. 14,and an agent will be considered effective in treatment of tension-typeheadache according to the present invention, if it is capable ofpreventing or substantially preventing pain in connection withtension-type headache when pain scores after administration of theagent, when differering most from the corresponding score afteradministration of placebo, are at least 10% lower than scores forplacebo, typically at least 20% lower, preferably at least 30% lower,more preferably at least 40% lower. For an evaluation as described here,the size of the participating groups of patients will be at least 5patients in each group, typically at least 7 patients in each group,preferably at least 10 patients in each group, more preferably at least12 patients in each group, even more preferably at least 15 patients ineach group.

[0154] Evaluation of the ability of an agent to provide an effectiveprevention of tension-type headache by interacting with neuronaltransmission according to the present invention can be performed asdescribed above except that the parameter measured and scored byheadache patients will typically be duration of pain or frequency ofpain in connection with tension-type headache in sufferers with anepisodic form of the disease.

[0155] In the practical treatment of a patient, the administration of anagent will normally be continued for at least one month, preferably atleast two months and more preferably at least three months and in manycases indefinitely in order to establish and maintain the normalizationwhich is aimed at. If the desired normalization occurs before one monthof treatment, it is certainly possible according to the invention todiscontinue the treatment, but this will increase risk of relapse and isnormally not preferred. The administration is performed using at leastone dose daily or at any rate substantially at least one dose daily(which means that the treatment is not outside the scope of theinvention if it is just interrupted one or perhaps even (but notpreferred) a few days), and the dose of the particular agent ispreferably adapted so that it will maintain a therapeutic plasma levelsubstantially at any time. Notwithstanding the above statement to theeffect that the administration may in many cases be performedindefinitely, it is contemplated that there will be cases where thetreatment period will be less than 10 years, such as less than 5 yearsor less than 2 years or even less than 1 year.

[0156] The interaction with neuronal transmission connected with painperception will normally be such an interaction with neuronaltransmission connected with second order nociceptive neurons whichinvolves substantially reducing excitation mediated through theinteraction between transmitter substances and their receptors on secondorder nociceptive neurons.

[0157] The above-mentioned interaction will normally involve a reductionof C-fiber, A-d-fiber and A-b-fiber input to the nociceptive secondorder neurons, through a substantial reduction of excitatory activity insynapses of C-fibers, A-d-fibers and A-b-fibers on second order neurons,said activity mediated through the interaction between the involvedtransmitter substances and their receptors on second order nociceptiveneurons.

[0158] The reduction of excitatory activity in synapses of C-fibers,A-d-fibers and A-b-fibers on second order neurons mediated through theinteraction between the involved excitatory transmitter substances andtheir receptors on second order nociceptive neurons will preferably beperformed by administration of an effective amount of at least one agentwhich a) substantially inhibits the production of said excitatorytransmitter substance, b) substantially inhibits the release of saidexcitatory transmitter substance, c) substantially counteracts theaction of said excitatory transmitter substance, and/or d) substantiallyinhibits the binding of said excitatory transmitter substance to itsrelevant receptors.

[0159] Important examples of such excitatory transmitter substances areselected from the group consisting of glutamate, nitric oxide,neurokinins (substance P, neurokinin A, neurokinin B and bradykinin),CGRP, adenosine working-through, A2 receptors, 5-HT when working through5-HT_(2,3) receptors and pituitary adenylate cyclase actvatingpolypeptide (PACAP).

[0160] Agents which can interact with neuronal transmission mediated byglutamate will typically comprise competitive or non-competitiveantagonists of ionotropic glutamate receptors, including NMDA, AMPA andkainate receptors. Interaction with glutamate neurotransmission can alsobe performed with antagonists at the glycine site of the NMDA receptorsor with antagonists or inverse agonists at modulatory sites such aspolyamine sites. Interaction with metabotropic glutamate receptors canbe performed with agonists or antagonists depending-on whether they arereceptors located pre or postsynaptically and whether they belong to theexcitatory type I receptors (mGluR1,5) or the inhibitory type II andtype III receptors (mGluR2,3 and mGluR4,6-8, respectively).

[0161] While sensitization of second order neurons is believed, asexplained above, to be an important cause of pain in connection withtension type headache, it is clear that other elements of neuronaltransmission may also play a significant role and in some cases even apredominant role as explained in the model described in connection withFIG. 1. Based on this recognition, another, more general, aspect of thepresent invention introduces, for the first time, the use of a number ofclasses of substances for treatment of tension type headache. Thisaspect relates to a method for treatment or prevention of tension-typeheadache in a person in need of such treatment, comprising administeringan amount of an agent which, in the peripheral and/or central nervoussystem, is effective to specifically interact with neuronal transmissionconnected with pain perception by

[0162] a) substantially antagonizing the action of glutamate, 5-HT,GABA, nitric oxide, nitric oxide synthase, guanylate cyclase, cyclicguanylate monophosphate (cGMP), CGRP, substance P, neurokinin A,neurokinin B, bradykinin, PACAB, adenosine, glycine, histamine,neurotrophins, Na⁺ ions or Ca²⁺ ion channels,

[0163] or by

[0164] b) substantially potentiating the action of adenosine, galanineor norepinephrine,

[0165] with the proviso that said agent is not ethyl2-amino-(4-fluorobenzylamino)-3-pyridylcarbamate or an arylglycineamidederivative as described herein.

[0166] An additional aspect of the present invention relates to a methodof treatment of tension-type headache comprising administering to aperson in need of such treatment an effective amount of an agent whichsubstantially inhibits the action of the enzyme nitric oxide synthase(NOS) and thereby reduces chronic pain in connection with tension-typeheadache. In many cases the effect of treatment of tension-type headachewith a NOS inhibitor will be exerted through a decrease in existingcentral sensitization, but also within the scope of the invention istreatment of tension-type headache with NOS inhibitors whose effect onthe reduction of pain in connection with tension-type headache ismediated through a mechanism not directly involving inhibition ofcentral sensitization. Such an alternative mechanism might possiblycomprise an alteration of pain modulation involving nitric oxide.

[0167] A very important aspect of the present invention is a method ofscreening a drug for the ability to alleviate a tension-type headachewhich comprises comparing the relationship of pain intensity to pressureintensity when the trapezoid muscle is palpated at different pressureintensities for (a) persons having tension-type headaches aftertreatment with the drug, and (b) persons having tension-type headaches,treated with a placebo, and determining if the relationship is altered.Also within the scope of the present invention is a method of screeninga drug for the ability to alleviate tension-type headache comprisingtesting said drug in one or more of the assays 1-13 described above anddetermining effect in the test organism according to each assay. Thetest organisms will typically be human patients and human controls orrelevant experimental animals, depending on the given assay.

[0168] In the following discussion of substances or groups ofsubstances, numbers in parenthesis refer to the correspondingly numberedstructural formulas in the formula sheets below. NMDA receptorantagonists competitive

CGS 19755 (1)

(R)-CPP (2)

(R)-CPPene (3)

LY 235959 (4) non-competitive

MK-801 (5)

Metapramine (6)

Amitriptyline (7)

Imipramine (8)

Desipramine (9)

Mirtazapine (10)

Venlafaxine (11)

Memantine (12)

Ketamine (13)

Norketamine (14)

Dextromethorphan (15)

Remacemide (16)

Ifenprodil (17)

Eliprodil (18)

Synthalin (19) Glycine antagonists (NMDA co-agonist site)

(R)-HA-966 (20)

7-CI-Kynurenic acid (21)

L-689,560 (22)

L-701,252 (23)

L-701,273 (24)

L-701,324 (25)

GV150526A (26)

ACPC (27)

MNQX (28)

ACEA 1021 (29)

DCQX (30)

Felbamate (31) AMPA receptor antagonists competitive

CNQX (32)

NBQX (33)

PNQX (34)

YM90K (35)

L-698,544 (36)

LY 215490 (37)

AMOA (38)

NS-257 (39) non-competitive

GYKI 52466 (40)

SYM 2206 (41) Kainic acid receptor antagonist

NS-102 (42) Metabotropic glutamate receptor ligands

4CPG (43)

UPF523 (44)

L-AP4 (45) Neurokinin A (NK₂) receptor antagonists

SR-48968 (46)

GR 159897 (47) Bradykinin receptor antagonistsD-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic Icatibant (48)

WIN 64338 (49) NO synthase inhibitors

L-NAME (50)

L-NMMA (51)

L-NIO (52)

L-NNA (53)

Dimethyl-L-arginine (54)

Thiocitruline (55)

(S)-Methylthiocitrulline (56)

7-Nitroindazole (57)

Potassium carboxy-PTIO (58)

TRIM (59)

Tirilazad (60)

Diphenyleneiodonium chloride (61)

Paroxetine (62) Guanylat cyclase inbibitor

ODQ (63) GABA-A receptor agonists

Gabapentin (64)

TACA (65)

Isonipenotic acid (66)

Midazolam (69)

Isoguvacine (67)

THIP (68) GABA uptake inhibitors

(±)-cis-4-Hydroxynipecotic acid (70)

Guvacine (71)

THPO (72)

SKF 89976-A (73)

Tiagabine (74)

NO-711 (75) GABA transaminase inhibitor

Vigabatrin (76) Adenosin receptor ligands

N⁶-Cyclopentyladenosine (77)

Adenosine (78)

Dipyridamole (79)

DMPX (80)

Dilazep (81) 5-HT_(2.3) receptor antagonists

Tropanserin (82)

Pizotyline (83) α-2 Receptor agonists

Clonidine (84)

Apracionidine (85)

Xylazine (86)

Dexmedetomidine (87) Na⁺ channel blockers

Lamotrigine (88)

Lifarizine (89)

Phenytoin (90)

Lubeluzole (91)

Riluzole (92)

Carbamazepine (93)

Lidocaine (94)

Tocainide (95)

Mexiletene (96) Ca²⁺ channel blockers

Flunarizine (97)

Fostedil (98)

[0169] Agents which inhibit neuronal transmission mediated by glutamate,in the central and/or peripheral nervous system, are capable of a)substantially inhibiting the production of glutamate, b) substantiallyinhibiting the release of glutamate, c) substantially counteracting theaction of glutamate and/or d) substantially inhibiting the binding ofglutamate to receptors for glutamate.

[0170] Examples of competitive NMDA receptor antagonists arenitrogen-containing heterocyclic compounds selected from diacidicpiperidines, such as CGS 19755 (1), diacidic piperazines, such as(R)-CPP (2) and (R)-CPPene (3), phosphono amino acids such as LY 235959(4) and derivatives of any of the above which are competitive NMDAantagonists or prodrugs thereof.

[0171] Examples of non-competitive NMDA receptor antagonists arepolycyclic amines, such as MK-801 (5); tricyclic antidepressants, suchas Metapramine (6), Amitriptyline (7), Imipramine (8), Desipramine (9),Mirtazapine (10) or Venlafaxine (11); adamantanamines, such as Memantine(12); arylcyclohexylamines, such as Ketamine (13); arylcyclohexylamines,such as Norketamine (14): opioid derivatives, such Dextromethorphan(15); glycylamides, such as Remacemide (16); piperidinylethanols, suchas Ifenprodil (17): piperidinylethanols, such as Eliprodil (18);diguanidines, such as Synthalin (19); γ-aminobutyric acid derivatives,such as Gabapentin (64); polycyclic amines, such as Pizotyline (83) orderivatives of any of the above which are non competitive NMDAantagonists or prodrugs thereof.

[0172] Mirtazapine (10) and Venlafaxine (11) are conventionally known tohave α-2 receptor antagonist effects, and their efficacy asantidepressants are thought to be exerted through a decrease innoradrenergic neutrotransmission. However, it is presently believed thatMirtazapine and Venlafaxine may also have an effect on glutamateneurotransmission, potentially as non-competitive NMDA receptorantagonists. It is through this mechanism that the two substances arepresumed to provide a method of treatment of tension-type headacheaccording to the present invention.

[0173] Examples of Glycine antagonists are aminopyrrolidinones, such as(R)-HA-966 (20); kynurenic acid derivatives, such as 7-Cl-Kynurenic acid(21); tetrahydroquinolines, such as L-689,560 (22); kynurenic acidderivatives, such as L-701,252 (23), L-701,273 (24), L-701,324 (25);indoles such as GV150526A (26); glycine derivatives, such as ACPC (27);quinoxalinediones, such as MNQX (28), ACEA 1021 (29) and DCQX (30);dicarbamates, such as Felbamate (31) and derivatives of any of the abovewhich are glycine antagonists or prodrugs thereof.

[0174] Examples of competitive AMPA receptor antagonists arequinoxalinediones, such as CNQX (32), NBQX (33), PNQX (34) and YM90K(35); dihydroquinolones, such as L-698,544 (36); diacidicdecahydroisoquinolines, such as LY 215490 (37); amino acid isoxazoles,such as AMOA (38); indoleoximes, such as NS-257 (39) and derivatives ofany of the above which are competitive AMPA receptor antagonists orprodrugs thereof.

[0175] Examples of non-competitive AMPA receptor antagonists are2,3-benzodiazepines, such as GYKI 52466 (40); phthalazines, such as SYM2206 (41) and derivatives of any of the above which are non-competitiveAMPA receptor antagonists or prodrugs thereof.

[0176] Examples of competitive kainate receptor antagonists areindoleoximes, such as NS-102 (42) and derivatives thereof which arecompetitive kainic acid receptor antagonists or prodrugs thereof.

[0177] Examples of metabotropic receptor agonists are phenylglycines,such as 4CPG (43); amino acid indanes, such as UPF523 (44); phosphonoamino acids, such as L-AP4 (45) and derivatives of any of the abovewhich are metabotropic glutamate receptor agonists or prodrugs thereof.

[0178] Agents which inhibit neuronal transmission mediated by 5-HT, inthe central and/or peripheral nervous system, are capable of a)substantially inhibiting the synthesis of 5-HT, b) substantiallyinhibiting the release of 5-HT, c) substantially counteracting theaction of 5-HT and/or d) substantially inhibiting the binding of 5-HT toexcitatory 5-HT 5-HT_(2,3) receptors.

[0179] Examples of 5-HT_(2,3) receptor antagonists are tropanderivatives, such as Tropanserin (82); polycyclic amines, such asPizotyline (83) and derivatives of any of the above which are 5HT_(2,3)receptor antagonists or prodrugs thereof.

[0180] It is presently believed that Pizotyline (83) may also haveeffect on glutamate neurotransmission, potentially as a non-competitiveNMDA receptor antagonist, as mentioned above. This mechanism ispresumed, in addition to the 5-HT receptor antagonism, to provide amethod of treatment of tension-type headache according to the presentinvention.

[0181] Agents which can inhibit neuronal transmission mediated byadenosine, in the central and/or peripheral nervous system, are capableof a) substantially inhibiting the synthesis of adenosine, b)substantially inhibiting the release of adenosine, c) substantiallycounteracting the action of adenosine, and/or d) substantiallyfunctioning as antagonists at adenosine A2 receptors.

[0182] Examples of adenosine A2 receptor antagonists are xanthinederivatives, such as DMPX (80) and derivatives thereof which are A2receptor antagonists or prodrugs thereof.

[0183] Examples of adenosine uptake inhibitors are homopiperazinederivatives, such as Dilazep (81) and derivatives thereof which areadenosine uptake inhibitors or prodrugs thereof.

[0184] Agents which can inhibit neuronal transmission mediated bysubstance P, in the central and/or peripheral nervous system are capableof a) substantially inhibiting the synthesis of substance P, b)substantially inhibiting the release of substance P, c) substantiallycounteracting the action of substance P, and/or d) substantiallyinhibiting binding of substance P to receptors for substance P.

[0185] Agents which can inhibit neuronal transmission mediated byneurokinin A, in the peripheral and/or central nervous system, arecapable of a) substantially inhibiting the synthesis of neurokinin A, b)substantially inhibiting the release of neurokinin A, c) substantiallycounteracting the action of neurokinin A, and/or d) substantiallyinhibiting binding of neurokinin A to receptors for neurokinin A (NK₂receptors).

[0186] Examples of neurokinin A (NK₂) receptor antagonists arepeptidomimetics, such as SR-48968 (37); peptidomimetics, such as GR159897 (38) and derivatives thereof which are NK2 receptor antagonistsor prodrugs thereof.

[0187] Agents which can inhibit neuronal transmission mediated bybradykinin, in the peripheral and/or central nervous system, are capableof a) substantially inhibiting the production of bradykinin, b)substantially inhibiting the release of bradykinin, c) substantiallycounteracting the action of bradykinin and/or d) substantiallyinhibiting binding of bradykinin to receptors for bradykinin.

[0188] Examples of bradykinin receptor antagonists are peptidomimetics,such as Icatibant (48) and WIN 64338 (49) and derivatives of any of theabove which are bradykinin receptor antagonists or prodrugs thereof.

[0189] Agents which can inhibit neuronal transmission mediated by CGRP,in the peripheral and/or central nervous system, are capable of a)substantially inhibiting the production of CGRP, b) substantiallyinhibiting the release of CGRP, c) substantially counteracting theaction of CGRP and/or d) substantially inhibiting the binding of CORP toreceptors for CGRP.

[0190] Examples of GCRP receptor antagonists are GCRP 8-37.

[0191] Agents which can inhibit neuronal transmission mediated by PACAP,in the peripheral and/or central nervous system are capable of a)substantially inhibiting the synthesis of PACAP, b) substantiallyinhibiting the release of PACAP, c) substantially counteracting theaction of PACAP and/or d) substantially inhibiting binding of PACAP toreceptors for PACAP.

[0192] Agents which can inhibit neuronal transmission mediated by nitricoxide, in the peripheral and/or central nervous system, are capable ofa) substantially inhibiting the production of nitric oxide, b)substantially counteracting the action of nitric oxide, c) substantiallyinhibiting the production of nitric oxide synthase (NOS) and/or d)substantially counteracting the action of nitric oxide synthase (NOS).

[0193] The interaction with neuronal transmission connected with painperception connected with second order nociceptive neurons can compriseinteraction with intracellular substances involved in this neuronaltransmission, said interaction involving excitation mediated through theinteraction with enzymes and second messengers in second ordernociceptive neurons.

[0194] Preferred examples of the above mentioned intracellularsubstances are NOS, guanylate cyclase, and cGMP.

[0195] The interaction with neuronal transmission connected with painperception, comprising interaction with NOS will preferably be performedby the administration of an effective amount of at least one agent whichcan substantially inhibit the production of the NOS, and/orsubstantially counteract the action of NOS.

[0196] Examples of NOS inhibitors are arginine derivatives, such asL-NAME (50), L-NMMA (51), L-NIO (52), L-NNA (53) and Dimethyl-L-arginine(54); citrulline derivatives, such as Thiocitrulline (55) and(S)-Methylthiocitrulline (56); indazoles, such as 7-Nitroindazole (57);imidazolin-N-oxides, such as Potassium carboxy-PTIO (58);phenylimidazoles, such as TRIM (59); 21-aminosteroids, such as Tirilazad(60); biphenyls, such as Diphenyleneiodinium chloride (61); piperidinederivatives, such as Paroxetine (62) and derivatives of any of the abovewhich are NOS inhibitors or prodrugs thereof.

[0197] The interaction with neuronal transmission connected with painperception, comprising interaction with guanylate cyclase can beperformed by the administration of an effective amount of at least oneagent which substantially inhibits the production of guanylate cyclaseand/or substantially counteracts the action of guanylate cyclase.

[0198] Examples of guanylate cyclase inhibitors are quinoxalines, suchas ODQ (63) and derivatives thereof which are guanylate cyclaseinhibitors.

[0199] The interaction with neuronal transmission connected with painperception comprising interaction with cGMP can be executed by theadministration of an effective amount of at least one agent which, inthe peripheral and/or central nervous system, is capable of a)substantially inhibiting the production of guanylate cyclase, b)substantially counteracting the action of guanylate cyclase, c)substantially inhibiting the production of cyclic guanylatemonophosphate (cGMP), d) substantially counteracting the action ofcyclic guanylate monophosphate (cGMP) and/or e) substantially inhibitingany further steps in the reaction induced by cyclic guanylatemonophosphate (cGMP), such as protein kinase C.

[0200] The activity of C-fibers, A-d-fibers and A-b-fibers on secondorder nociceptive neurons involves inhibitor neurotransmittersubstances. Reduction of activity of C-fibers on second order neuronsHill normally be performed by administration of an effective amount ofat least one agent which is capable of a) substantially inhibiting theenzymatic degradation of said inhibitory transmitter substance, b)substantially enhancing the release of said inhibitory transmittersubstance, c) substantially enhancing the action of said inhibitorytransmitter substance and/or substantially activating the relevantreceptor for said inhibitory transmitter substance.

[0201] Preferred examples of such inhibitory transmitter substances areselected from the group consisting of GABA, galanine, adenosine workingthrough A¹ receptors, and norepinephrine.

[0202] Agents which can stimulate neuronal transmission mediated byGABA, in the peripheral and/or central nervous system, are capable of a)substantially enhancing the production of GABA, b) substantiallyinhibiting the enzymatic degradation of GABA, c) substantially enhancingthe release of GABA, d) substantially enhancing the action of GABAand/or e) substantially activating receptors for GABA.

[0203] An example of a substance with GABA-enhancing activity isbenzodiazepines, such as Midazolam (69) and derivatives thereof whichare GABA activity enhancers or prodrugs thereof.

[0204] Examples of GABA-A receptor agonists are γ-aminobutyric acidderivatives, such as Gabapentin (64) and TACA (65): Isonipecotic acid(66) and Isoguvacine (67); 3-hydroxylisoxazoles, such as THIP (68) andderivatives of any of the above which are GABA-A agonists or prodrugsthereof.

[0205] Gabapentin is conventionally known to have GABA-A receptoragonist activity, though this mechanism has been questioned. However, itis presently believed that Gabapentin may also have antagonist effect onglutamate transmission, indirectly or directly, potentially as anon-competitive NMDA receptor antagonist, as mentioned above. It isthrough this mechanism, in addition to its gabaergic activity, thatGabapentin is presumed to provide a method of treatment of tension-typeheadache according to the present invention.

[0206] Examples of GABA uptake inhibitors are carboxypiperidinederivatives, such as (±)-cis-4-Hydroxynipecotic acid (70);carboxypyridine derivatives, such as Guvacine (71); 3-hydroxyisoxazoles,such as THPO (72); nipecotic acid derivatives, such as SKF 89976-A (73)and Tiagabine (74); guvacine derivatives, such as NO-711 (75) andderivatives of any if the above which are GABA uptake inhibitors orprodrugs thereof.

[0207] Examples of GABA transaminase inhibitors are γ-aminobutyric acidderivatives, such as Vigabatrin (76) and derivatives thereof which areGABA transaminase inhibitors or prodrugs thereof.

[0208] Agents which can stimulate neuronal transmission mediated bygalanine, in the peripheral and/or central nervous system, are capableof a) substantially inhibiting the enzymatic degradation of galanine, b)substantially enhancing the release of galanine, c) substantiallyenhancing the action of galanine and/or d) substantially functioning asagonists at galanine receptors.

[0209] Agents which can stimulate neuronal transmission mediated byadenosine, in the peripheral and/or central nervous system, are capableof a) substantially inhibiting the enzymatic degradation of adenosine,b) substantially enhancing the release of adenosine, c) substantiallyenhancing the action of adenosine and/or d) substantially functioning asagonists at A¹receptors.

[0210] Examples adenosine A¹ receptor agonists are adenosinederivatives, such as N⁵-Cyclopentyladenosine (77); adeninglucosides,such as Adenosine (78) and derivatives thereof which are A1 receptoragonists or prodrugs thereof.

[0211] An example of an enhancer of the action of adenosine ispyrimidine derivatives, such as Dipyridamole (79) and derivativesthereof which are adenosine uptake inhibitors or prodrugs thereof.

[0212] Agents which can stimulate neuronal transmission mediated bynorepinephrine, in the peripheral and/or central nervous system, arecapable of a) substantially inhibiting the enzymatic degradation ofnorepinephrine, b) substantially enhancing the release ofnorepinephrine, c) substantially enhancing the action of norepinephrineand/or c) substantially functioning as agonists at norepinephrine α-2receptors.

[0213] Examples of a-2 receptor agonists are aminoimidazolines, such asClonidine (84); aminoimidazolines, such as Apraclonidine (85);thiazinamines, such as Xylazine (86); imidazoles, such asDexmedetomidine (87) and derivatives of any of the above which are α-2receptor agonists or prodrugs thereof.

[0214] Reduction of activity of C-fibers on second order nociceptiveneurons can be performed by administration of an effective amount of atleast one agent which substantially blocks ion channels for Na⁺ or Ca²⁺ions.

[0215] Examples of Na⁺ channel blockers are triazines, such asLamotrigine (88); diphenylmethylpiperazines, such as Lifarizine (89);hydantoins, such as Phenytoin (90); aminopiperidines, such as Lubeluzole(91); benzthiazoles, such as Riluzole (92); dibenzazepines, such asCarbamazepine (93); phenylamides, such as Lidocaine (94); phenylamides,such as Tocainide (95); aminoethylanisoles, such as Mexiletene (96) andderivatives of any of the above which are Na⁺ channel blockers orprodrugs thereof.

[0216] Examples of Ca²⁺ channel blockers are diphenylmethylpiperazines,such as Flunarizine (97); arylphosphonic esters, such as Fostedil (98)and derivatives of any of the above which are Ca²⁺ channel blockers orprodrugs thereof.

[0217] In accordance with normal usage, the term “agent”, as usedherein, is intended to designate an active substance per se, whetheradministered as such or in the form of a prodrug thereof, as well as apharmaceutical composition comprising the substance or prodrug.

[0218] In addition to the specific substances mentioned above,derivatives thereof which show an activity of the same kind as thesubstance specifically mentioned are also useful for the purpose of thepresent invention. The kind of derivatives which come into considerationwill, of course, depend on the specific character of the substance inquestion, but as general examples of derivatives which may be relevantfor many of the substances may be mentioned introduction of or chance ofalkylsubstituents (typically with a chain length from one to five carbonatoms) on aliphatic chains, cycloalkanes, aromatic and heterocyclic ringsystems, introduction of or change of substituents such as halogens ornitro groups, change of ringsize for cycloalkanes, change of aromatic orheterocyclic ringsystems, change of alkylsubstituents on O- and N-atoms,change of the alcohol part of ester groups, and bioisosteric replacementof functional groups, especially use of carboxylic acid bioisosteressuch as phosphonic acids, phosphinic acids, tetrazoles,3-hydroxyisoxazoles, sulphonamiders and hydroxyamic acids. Salts ofacidic or basic compounds will be equally useful compared to the freeacids or free bases. In case of racemic compounds, can racemates as wellas pure enantiomeres and diastereoisomeres be used, and in the case ofsubstances interacting with antagonist action be required. Of course,derivatives to be used should be derivatives which, in addition to theirdesired activity, show an acceptably low toxicity, and, in general, thederivates should, just as the substances themselves, be pharmaceuticallyacceptable.

[0219] The agent used according to the invention may be administered assuch or in the form of a suitable prodrug thereof. The term “prodrug”denotes a bioreversible derivative of the drug, the bioreversiblederivative being therapeutically substantially inactive per se but beingable to convert in the body to the active substance by an enzymatic ornon-enzymatic process.

[0220] Thus, examples of suitable prodrugs of the substances usedaccording to the invention include compounds obtained by suitablebioreversible derivatization of one or more reactive or derivatizablegroups of the parent substance to result in a bioreversible derivative.The derivatization may be performed to obtain a higher bioavailabilityof the active substance, to stabilize an otherwise unstable activesubstance, to increase the lipophilicity of the substance administered,etc.

[0221] Examples of tapes of substances which may advantageously beadministered in the form of prodrugs are carboxylic acids, other acidicgroups and amines, which may be rendered more lipophilic by suitablebioreversible derivatization. As examples of suitable groups may bementioned bioreversible esters or bioreversible amides. Amino acids aretypical examples of substances which, in their unmodified form, may havea low absorption upon administration. Suitable prodrug derivatives ofamino acids will be one or both of the above-mentioned types ofbioreversible derivatives.

[0222] For the administration to a patient, a substance having any ofthe activities as defined above or a prodrug thereof is preferablyformulated in a pharmaceutical composition containing one or moresubstances having any of the activities as defined above or prodrugsthereof and one or more pharmaceutically acceptable excipients.

[0223] The substance or substances to be administered may be formulatedin the compositions in pharmaceutically acceptable media, the characterof which are adapted to the chemical character of the substance. Thecompositions may be adapted for administration by any suitable method,for example by oral, buccal, sublingual, nasal, rectal or transdermaladministration. Substances which are suitable for oral administrationmay be formulated as liquids or solids, such as syrups, suspensions oremulsions, tablets, capsules and lozenges. A liquid compositions willnormally comprise a suspension or solution of the substance in asuitable liquid carrier or suitable liquid carriers, for example anaqueous solvent such as water, ethanol or glycerol, or a non-aqueoussolvent, such as polyethylene glycol or an oil. The composition may alsocontain a suspending agent, preservative, flavouring or colouring agent.A composition in the form of a tablet can be made using any suitablepharmaceutical carrier or carriers used for preparing solidformulations, for example pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, talcum, cellulose,glucose, sucrose, magnesium carbonate, and the like. For oraladministration, a pharmaceutically acceptable non-toxic composition maybe formed by incorporating normally used excipients, such as thosecarriers previously listed, and generally 1-95% of active ingredient,that is, a substance used according to the invention or a prodrugthereof, often preferably 25-75% of the substance of the prodrug. Acomposition iii the form of a capsule can be prepared using conventionalencapsulation procedures. Thus, e.g., pellets containing the substanceor prodrug in question may be prepared using any suitable carriers andthen filled into a hard gelatin capsule, or a dispersion or suspensioncan be prepared using any suitable pharmaceutical carrier or carriers,such as aqueous gums, celluloses, silicates or oils and the dispersionor suspension can be filled into a soft gelatin capsule.

[0224] Examples of parenteral compositions are solutions or suspensionsof the substances or prodrugs in a sterile aqueous carrier orparenterally acceptable oil, such as polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil. The compositions maycontain pharmaceutically acceptable auxiliary substances as required toapproximate physiological conditions, such as buffering agents, wettingagents, detergents, and the like. Additives may also include additionalactive ingredients, e.g. bactericidal agents, or stabilizers. Ifdesired, the solution or suspension can be lyophilized and reconstitutedwith a suitable carrier such as a sterile aqueous carrier prior toadministration.

[0225] Compositions for nasal administration can be formulated, e.g., asaerosols, drops, gels and powders. For aerosol administration, thesubstance or prodrug is preferably supplied in finely divided form alongwith a surfactant and propellant. Typical percentages of the substanceor prodrug are 0.01-20% by weight, preferably 1-10%. The surfactantmust, of course be non-toxic, and preferably soluble in the propellant.Representative of such surfactants are the esters or partial esters offatty acids containing from 6 to 22 carbon atoms, such as caproic,octanoic, lauric, palmitic, stearic, linoleic, linoleic, olesteric andoleic acids with an aliphatic polyhydric alcohol or its cyclic anhydridesuch as, for example, ethylene glycol, glycerol, erythritol, arbitol,mannitol, sorbitol, the hexitol anhydrides derived from sorbitol, andthe polyoxyethylene and polyoxypropylene derivatives of these esters.Mixed esters, such as mixed or natural glycerides may be employed. Thesurfactant may constitute 0.1-20% by weight of the compositionpreferably 0.25-5%. The balance of the composition is ordinarilypropellant. Liquified propellants are typically gases at ambientconditions, and are condensed under pressure. Among suitable liquifiedpropellants are the lower alkanes containing up to 5 carbons, such asbutane and propane; and preferably fluorinated or fluorochlorinatedalkanes. Mixtures of the above may also be employed. In producing theaerosol, a container equipped with a suitable valve is filled with theappropriate propellant, containing the substance according to theinvention and surfactant. The ingredients are thus maintained at anelevated pressure until released by action of the valve.

[0226] Compositions for buccal or sublingual administration are, forexample, tablets, lozenges and pastilles, in which the substance or theprodrug is formulated with a carrier such as sugar and acacia,tragacanth or gelatin and glycerol. Compositions for rectaladministration are suitably in the form of suppositories containing asuppository base such as cocoa butter. Compositions for transdermalapplication are for example ointments, gels and transdermal patches.

[0227] The compositions are preferably in unit dosage form such as atablet capsule or ampoule. Each dosage unit for oral administration willnormally contain from 1 to 500 mg (and for parenteral administrationpreferably from 0.1 to 25 mg) of a substance used according to theinvention or a prodrug therefor, calculated as the free activesubstance.

[0228] The physiologically acceptable substances or prodrugs arenormally administered in a daily dosage of between 1 mg and 500 mg for aadult person, usually between 10 mg and 400 mg, such as between 10 mgand 250 mg orally or an intravenous, subcutaneous or intramuscular doseof between 0.1 mg and 100 mg, preferably between 0.1 and 50 mg, such asbetween 1 mg and 25 mg of the substance. The substance or prodrug ispreferably administered 1 to 4 times daily. As mentioned above, theadministration is normally aimed at maintaining a therapeuticallyeffective serum concentration of the substance for at least one month,preferably at least two months or at least three months. Controlledrelease tape compositions will often be suitable for maintaining aneffective serum concentration with a small number of daily unit dosages.

LEGENDS TO FIGURES

[0229]FIG. 1 shows the model for the development of tension-typeheadache.

[0230] Abbreviations; V: Trigeminal nerve, C2 and C3. Second and thirdcervical segment of the spinal cord. PAG: Periaquaductal grey, DRN:Dorsal raphe nuclei, on-cells: cells in ventromedial medulla, whichactivate pain pathways, for instance by reducing the threshold in thetail flick test. C: C fibers. Ad: A-d-fibers. Ab: A-b-fibers.

[0231]FIG. 2 depicts stimulus-response functions in trapezius muscle.

[0232] Stimulus-response functions for pressure versus pain in thetrapezius muscle in 40 patients with chronic tension-type headache(dots) and in 40 control subjects (triangles)(mean ±SE). Patients weresignificantly more tender than controls, P=0.002. In patients, thestimulus-response function was approximately linear with a slope(b)=0.50±0.04 mm/U, P=0.00004 (FIG. 2A). In contrast pain intensitiesincreased in a positively accelerating fashion with increasing pressureintensities in controls, a relation that was well described by a powerfunction. This was demonstrated by obtaining an approximately linearrelation between pressure and pain in a double logarithmic plot,b=3.8±0.61 logmm/logU, P=0.002 (FIG. 2B).

[0233]FIG. 3 depicts stimulus-response functions in temporal muscle.

[0234] Stimulus-response functions for pressure versus pain in thetemporal muscle in 40 patients (dots) and in 40 controls (triangles)(mean ±SE). Patients were slightly more tender than controls, but thedifference was not statistically significant, P=0.42. In both groupspain intensities increased in a positively accelerating fashion withincreasing pressure intensities. This was demonstrated by obtainingapproximately linear relations between pressure and pain in a doublelogarithmic plot: patients b=3.0±0.36 logmm/logU. P=0.0002; controlsb=6.7±0.36 logmm/logU, P=0.00001 (FIG. 3B).

[0235]FIG. 4 depicts stimulus-response functions in trapezius muscle.

[0236] Stimulus-response functions for pressure versus pain in thetrapezius muscle in the 20 most tender patients (diamonds) and in the 20least tender patients (squares)(mean ±SE). In the most tender patients,the stimulus-response function was linear, b=0.69±0.03 mm/U, P<0.00001.In contrast, pain intensities increased in a positively acceleratingfashion with increasing pressure intensities in the least tenderpatients. This was demonstrated by obtaining a linear relation betweenpressure and pain in a double logarithmic plot, b=4.0±0.18 logmm/logU,P<0.00001 (FIG. 4B).

[0237]FIG. 5 shows Total Tenderness Scores in patients.

[0238] The Total Tenderness Scores (TTS) in patients outside and duringa headache episode and in controls. Median values are given (***indicate p<10⁻⁵ and ** indicate p=0.01, Wilcoxon's test).

[0239]FIG. 6 shows Pressure Pain Thresholds (PPDT) and Pressure PainTolerances (PPTO) in patients. Pressure Pain Thresholds (PPDT) andPressure Pain Tolerances (PPTO) in patients outside (closed bars) andduring a headache episode (open bars). Mean values of left and rightside are given in kPa with SD as vertical bars (* indicate p<0.05,Wilcoxon's test).

[0240]FIG. 7 shows thermal thresholds in the hands and temporal (Temp)regions of patients.

[0241] Thermal thresholds in the hands and temporal (Temp) regions ofpatients outside (closed bars) and during a headache episode (openbars). WD indicate warmth detection, HPD heat pain detection and HPTOheat pain tolerance thresholds. Mean values of left and right side aregiven in ° C. with SD as vertical bars (* indicate p<0.05, Wilcoxon'stest).

[0242]FIG. 8 depicts EMG-amplitude levels from the temporal andtrapezius muscles of patients. EMG-amplitude levels from the temporaland trapezius muscles of patients outside (closed bars) and during aheadache episode (open bars). Part A indicates the resting condition andpart B the maximal voluntary contraction. Mean values of left and nightside are given in uV with SD as vertical bars.

[0243]FIG. 9 depicts pain intensities in patients and controls.

[0244] Pain intensities in those patients (filled circles) and controls(open circles) who developed tension-type headache after a 30 minutessustained clenching procedure. The ordinate indicates the mean painintensity in mm as recorded on a 100 mm visual analogue scale. Theabscissa indicates the time after the clenching procedure (* p<0.05,Mann-Whitney's test)

[0245]FIG. 10 shows Total Tenderness Scores (TTS) in patients and incontrols.

[0246] Total Tenderness Scores (TTS) in patients and in controls beforeand 90 minutes after experimental tooth clenching with respect todevelopment of headache. Median values with quartiles are given. (**indicate p<0.01, *** p<0.003, Wilcoxon's test).

[0247]FIG. 11 shows Pressure Pain Detection Thresholds and Pressure PainTolerances in patients and controls.

[0248] Part A shows the Pressure Pain Detection Thresholds and Part Bthe Pressure Pain Tolerances from fingers (F), temporal (T) and parietal(P) regions from patients and controls before (filled bars) and afterclenching (open bars) with respect to development of headache Meanvalues of right and left side with SD are given in kPa. (* indicatep<0.05, as p<0.01, Wilcoxon's test).

[0249]FIG. 12 shows thermal thresholds in the temporal region ofpatients and controls.

[0250] Thermal thresholds in the temporal region of patients andcontrols before (filled bars) and after clenching (open bars) withrespect to headache development. WD indicate warmth detection, PD heatpain detection and PTO heat pain tolerance. Mean values of right andleft side with SD are given in ° C.

[0251]FIG. 13 shows EMG-amplitudes in temporal and trapezius muscles ofpatients and controls.

[0252] Part A shows the EMG-amplitudes (Root Mean Square-values) duringresting condition and part B during the maximal voluntary contraction intemporal (temp) and trapezium (trap) muscles from patients and controlsbefore (filled bars) and after clenching (open bars) with respect toheadache development. Mean values of left and right side with SD aregiven in uV (* indicate p<0.05, ** p<0.01 and p<0.001, Wilcoxon's test).

[0253]FIG. 14 shows changes in pain intensity and treatment.

[0254] Post infusion changes in pain intensity (VAS) relative topre-treatment pain intensity in 16 patients with chronic pain. L-NMMAreduced pain significantly more than placebo (p=0.007).

[0255]FIG. 15 shows Pressure Pain Thresholds (PPDT) and Pressure PainTolerances (PPTO) in patients with chronic tension-type headacheassociated with muscular disorders (MUS) (filled bars) or unassociatedwith such disorders (non-MUS) (open bars). Mean values from the fingers,temporal (Temp) and Parietal (Par) regions are given in kPa with SE asvertical bars

[0256] (*** indicate p<0.001,* indicate p=0.04).

[0257]FIG. 16 shows Pressure Pain Thresholds (PPDT) and Pressure PainTolerances (PPTO) in patients with episodic tension-type headacheassociated pith muscular disorders (MUS) (filled bars) or unassociatedwith such disorders (non-MUS) (open bars). Mean values from fingers,temporal (Temp) and Parietal (Par) regions are given in kPa with SE asvertical bars.

[0258] No significant differences were detected.

[0259]FIG. 17 shows the percentage of change in muscle hardness. Musclehardness was significantly more reduced following treatment with L-NMMA(dots) than with placebo (triangles) in patients with chronic myofascialpain. * denotes p<0.05 compared with baseline (time=0). The plotsrepresent mean scores.

[0260]FIG. 18 shows the percentage of change in Total Tenderness Scoring(TTS). The TTS tended to be reduced following treatment with L-NMMA(dots) compared with placebo (triangles) (p=0.11). Within eachtreatment, the TTS was significantly reduced at 60 and 120 minutes afterstart of the infusion of L-NMMA, while there was no significant changesat any time after treatment with placebo. ** denotes p<0.01 comparedwith baseline (time=0). The plots represent mean scores.

[0261]FIG. 19 shows the percentage of change from baseline painintensity on a 100 mm Visual Analog Scale. The pain intensity wassignificantly more reduced during treatment with L-NMMA (dots) than withplacebo (triangles) (p=0.006). * denotes p<0.05 compared with baseline(time=0). Tile plots represent mean scores (copyright from Lancet).

EXAMPLE 1

[0262] Experimental Evidence for Central Sensitization in ChronicMyofascial Pain

[0263] The study was performed in order to investigate thepathophysiology of myofascial tenderness, which has consistently beenreported to be increased in patients with tension-type headache (Lousand Olesen 1982; Langemark and Olesen 1987, Jensen et al. 1993b).Recently, it was suggested that myofascial tenderness may be the resultof a lowered pressure pain threshold, a stronger response to pressuresin the noxious range (as illustrated by a steeper stimulus-responsefunction) or a combination of both (Jensen 1990b). The aim of the studytherefore was to investigate the stimulus-response function for pressureversus pain in patients with tension-type headache. The methods and theresults of the study will be described in the following.

[0264] Materials and Methods Table III Clinical data on headachepatients and controls Patients Controls Number 40 40 Sex (Females/males)25/15 25/15 Age, years 40.0 (18-60) 39.8 (18-60) Frequency of TH, 24.6(16-28) <1 days/4 weeks

[0265] Patients and Controls

[0266] Forty patients with chronic tension-type headache diagnosedaccording to the criteria of the International Headache Society (1988)were examined during a typical episode of tension-type headache (TableIII). Seven patients with coexisting infrequent migraine (<oneday/month) were accepted. The patients were recruited from theout-patient headache clinic at Glostrup Hospital without respect topresence or absence of myofascial tenderness. All patients undercount ageneral physical and a neurological examination and completed adiagnostic headache diary (Russell et al. 1992) during a 4-week run-inperiod. The patients were not allowed to take analgesics on the day ofexamination. Patients suffering from serous somatic or psychiatricdiseases and abusers of analgesics were excluded. Forty healthy, age-and sex-matched volunteers served as controls. Only controls who did nothave a headache on the day of examination and had less than 12 days withheadache a year were used. All subjects gave written informed consent toparticipate in the study, which was approved by the local ethicscommittee.

[0267] Apparatus

[0268] A palpometer (Bendtsen et al. 1994) was used to investigate thestimulus-response function for pressure versus pain. The palpometerconsists of a Force Sensing Resistor™ (FSR) connected to a meter, aprinciple first described by Atkins et al. (Atkins et al. 1992). The FSRis a commercially available polymer film device, which exhibits adecreasing electrical resistance pith increasing force applied to thedevice. If the force is concentrated on a small area the resistance isfurther decreased, i.e. the properties of the FSR lies somewhere betweena force transducer and a pressure transducer. The FSR is 0.33 mm thickand circular with a diameter of 10 mm. The FSR is attached with thinadhesive tape (Micropore®) to the tip of the palpating finger. The forceapplied to the FSR is displayed on the meter scale, which is dividedinto arbitrary units from 60 to 200 arbitrary units (U). To improve thereadability of the meter, the readout is filtered using a low-passfilter. The relation between the forces applied to the plastic film andthe palpometer output is linear in the range from 80 to 200U (Bendtsenet al. 1994). This range is equivalent to a force range from 235 gm to1550 gm. The intra- and inter-observer variations for recordings ofpressure intensity have previously found to be 3.1% and 7.2%,respectively (Bendtsen et al. 1994). Detailed information on thepalpometer has been published earlier (Bendtsen et al. 1994).

[0269] Methods

[0270] The examination was performed in a standardized manner by thesame investigator, a trained technician (HA), throughout the wholestudy. The subjects were examined sitting in a dental chair withheadrest.

[0271] Total Tenderness

[0272] Tenderness of specified pericranial regions was recordedaccording to the Total Tenderness Scoring system, which has previouslyproved to be reliable (Bendtsen et al. 1995a). Five pairs of muscles(masseter, temporal, frontal, sternocleidomastoid and trapezius muscles)and three pairs of tendon insertions (coronoid and mastoid processes andneck muscle insertions) were palpated. Palpation was performed withsmall rotating movements of the observer's second and third fingers.Pressure was sustained for 4-5 seconds. Prior to the study, thepalpometer was used to train the observer to exert a palpation pressureof moderate intensity (140 U). The tenderness was scored on a 4-point(0-3) scale as follows: 0=denial of tenderness, no visible reaction;1=verbal report of discomfort or mild pain, no visible reaction 2=verbalreport of moderate pain, with or without visible reaction; 3=verbalreport of marked pain and visible expression of discomfort. The valuesfrom left and right sides were summed to a Total Tenderness Score(maximum possible score=48).

[0273] Stimulus-Response Functions

[0274] Stimulus-response functions for pressure versus pain wererecorded during pressure-controlled palpation. i.e. palpation withcontrolled pressure intensity by means of the palpometer.Pressure-controlled palpation has previously proved to be a reliablemethod of tenderness recording (Bendtsen et al. 1995a). Palpation wasperformed with small rotating movements of the observer's second finger.Pressure was sustained for 4-5 seconds. The subjects were palpated atthe trapezius and temporal muscles at the non-dominant side. Thesemuscles haste previously been found to represent a highly tender and alargely normal muscle respectively in patients with tension-typeheadache (Jensen et al. 1993b). Palpation was performed with sevendifferent pressure intensities chosen in random order in the range from80 to 200 U. At each pressure intensity the subject indicated thecorresponding pain intensity on a visual analogue scale blinded for theobserver. The visual analogue scale consisted of a 100-mm line withendpoints designated “no pain” and “unbearable pain”: The degree oftenderness elicited in each subject was calculated as the area under thestimulus-response curve (AUC) according to the trapezium rule (Matthewset al. 1990).

[0275] Statistics

[0276] Results are presented as mean ±SE. Data were analyzed withMann-Whitney's test and simple linear regression. Five percent wasaccepted as level of significance.

[0277] Results

[0278] Total Tenderness

[0279] The Total Tenderness Score in patients was 17.7±1.7 andsignificantly higher than 3.4±0.53 in controls, p<0.00001.

[0280] Stimulus-Response Functions

[0281] The stimulus-response functions for pressure versus pain in thetrapezius muscle in patients and in controls are shown in FIG. 2.Calculating the area under the stimulus-response functions revealed thatpatients were significantly more tender (AUC=3370±423 mmU) than controls(AUC=1693±269 mmU), P=0.002. In controls, pain intensities increased ina positively accelerating fashion with increasing pressure intensities.The stimulus-response function was well described by a power function.This was demonstrated by obtaining an approximately linear relationbetween pressure and pain in a double logarithmic plot, slope(b)=3.8±0.61 logmm/logU, P=0.002 (FIG. 2B). In contrast, thestimulus-response function was approximately linear in patients,b=0.50±0.04 mm/U, P=0.00004. Thus, the stimulus-response functions incontrols and in patients were qualitatively different.

[0282] The stimulus-response functions for pressure versus pain in thetemporal muscle are shown in FIG. 3. Patients were slightly more tender(AUC=2139±327 mmU) than controls (AUC=1722±257 mmU), but the differencewas not statistically significant, P=0.42. In controls, pain intensitiesincreased in a positively accelerating fashion with increasing pressureintensities. In a double logarithmic plot the relation between pressureand pain was linear, b=6.7±0.36 logmm/logU, P=0.00001 (FIG. 3B). Inpatients, pain intensities increased in a positively acceleratingfashion with increasing pressure intensities. However, the curve wasirregular partly resembling a linear function. The regression functionwas approximately linear in a double logarithmic plot b=3.0±0.36logmm/logU, P=0.0002 (FIG. 3B).

[0283] To explore whether the abnormal stimulus-response function in thetrapezius muscle was related to the increased tenderness or to thediagnosis of tension-type headache, the patients were subgrouped on thebasis of their degree of tenderness. The stimulus-response functions forthe 20 most tender patients (AUC=5359±538 mmU) and for the 20 leasttender patients (AUC=1381±176 mmU) are shown in FIG. 4. In the 20 mosttender patients, the stimulus-response function was linear, b=0.69±0.03mm/U, P<0.00001. In contrast, pain intensities increased in a positivelyaccelerating fashion with increasing pressure intensities in the 20least tender patients. In a double logarithmic plot the relation betweenpressure and pain was linear, b=4.0±0.18 logmm/logU, P<0.00001 (becausenone of the patients reported any pain at the lowest stimulus intensity(U=80), a value of 1 mm was added to all pain intensities in order toperform this analysis) (FIG. 4B).

[0284] Discussion

[0285] Possible physiological mechanisms leading to myofascial paininclude: a) sensitization of peripheral myofascial nociceptors, b)sensitization of second order neurons at the spinal/trigeminal level, c)sensitization of supraspinal neurons, and d) decreased antinociceptiveactivity from supraspinal structures. These mechanisms may beinvestigated by relating the intensity of mechanical pressure applied todeep tissues to the response recorded from sensory neurons. Such studieson animal models have provided important information on deep tissue pain(Ness and Gebhart 1987; Cervero and Sann 1989; Yu and Mense 1990; Jänigand Koltzenburg 1991), but till now the relation between pressure andpain has not been investigated in patients with chronic myofascial pain.

[0286] Previously the stimulus-response function for-pressure versuspain had been studied in 30 subjects with tender pericranial muscles (15headache patients and 15 volunteers) (Bendtsen et al. 1995a). In thetrapezius muscle, an approximately linear stimulus-response functionvirtually identical to the one recorded in patients in the present studywas found. The finding of almost identical results in two different butcomparable populations obtained by two different observers, indicatesthat the employed method for recording of stimulus-response functions isreliable.

[0287] Before the present investigation, the stimulus-response functionin normal muscle was expected by the inventors to be qualitativelysimilar to the stimulus-response ruction in tender muscle, i.e. linear,but with a less steep slope or with a parallel shift to the right ashypothesized by Jensen (Jensen 1990). Surprisingly, the relation betweenpalpation pressure and pain in normal muscle and in highly tender musclediffered markedly. In the trapezius and temporal muscles of controls,pain intensities increased in a positively accelerating fashion withincreasing pressure intensities, a relation that was well described by apower function. The same was found in patients in the temporal musclewhich was only slightly to moderately tender. The patients weresubgrouped on the basis of their degree of tenderness, thestimulus-response function was linear in the most tender patients, whileit was well described by a power function in the least tender patients.Thus, the stimulus-response function becomes increasingly linear withincreasing degrees of tenderness and die qualitatively changedstimulus-response function is related to actual tenderness and not tothe diagnosis of tension-type headache. The possibility that the linearstimulus-response function was due to a shift to the left of the normalstimulus-response function such that the patients were on the steep partof the curve already at low pressures can be excluded. If so, thepatients would have been much more tender than controls also at thelowest stimulus-intensities, which was not the case.

[0288] The present finding of a qualitatively altered response tonociceptor stimulation in tender muscle demonstrates for the first timethat myofascial pain has a physiological basis and that myofascial pain,at least in part, is caused by qualitative changes in the processing ofsensory information. These changes may be located to peripheral nerveendings, to the spinal cord or to higher order neurons.

[0289] Spinal dorsal horn neurons that receive input from deepmyofascial tissues can be classified as high-threshold mechanosensitive(HTM) neurons requiring noxious intensities of stimulation foractivation and as low-threshold mechanosensitive (LTM) neurons, whichare activated b) innocuous stimuli (Mense 1993). Yu and Mense (Yu andMense 1990) have shown that HTM dorsal horn neurons have a positivelyaccelerating stimulus-response function, whereas thestimulus-response-function of LTM neurons is approximately linear. Thisindicates that the linear stimulus-response function in tender humanmuscle may be caused by activity in LTM afferents. LTM afferents do notnormally mediate pain, but strong input from peripheral nociceptors canremodel the circuitry of the dorsal horn by unmasking previouslyineffective synapses and by forming novel synaptic contacts between LTMafferents and dorsal horn neurons that normally receive input from HTMafferents (Wall 1977; Wall and Woolf 1984; Cervero and Jänig 1992; Hu etal. 1992; Woolf et al. 1992; Dense 1993; McMahon et al. 1993; Mayer andGebhart 1994; Hoheisel et al. 1994). In this way LTM afferents canmediate pain (Woolf and Thompson 1991). While the above-mentionedstudies have been performed on animal models (Torebjörk et al. 1992).Torebjörk et al. have demonstrated similar changes in the centralprocessing of inputs from LTM afferents in humans following intradermalinjection of capsaicin. It therefore seems probable that the presentfindings can be explained by changes in neuronal behavior at thespinal/trigeminal level. Support for this explanation was provided by asimultaneous investigation of pain thresholds in the same subjects bymeans of an electronic pressure algometer. Patents had significantlylower pressure pain detection and tolerance thresholds in fingers thancontrols (Bendtsen et al. 1996a). This indicates that the painperception is centrally disturbed. A decrease of the supraspinaldescending inhibition probably does not explain the present findings,because it has been reported that the descending inhibition acts via aparallel shift or via a decreased slope of the stimulus-response curve(Ness and Gebhart 1987; Yu and Mense 1990), while it does not change theshape of the stimulus-response curve. Sensitization of normally activeperipheral-nociceptors would probably induce a quantitative rather thana qualitative change of the stimulus-response curve (Koltzenburg et al.1992).

[0290] The results thus demonstrate for the first time that nociceptiveprocesses are qualitatively altered in patients with chronictension-type headache, and that the central nervous system is sensitizedat the spinal/trigeminal level in these patients.

[0291] Recent Studies from the Present Inventors Indicating that theCentral Sensitization is Induced by Prolonged Muscle Pain

[0292] As mentioned above, the information obtained from basic painresearch suggests that the central sensitization in chronic tension-typeheadache is induced and probably maintained by prolonged noxious inputfrom the periphery. Prolonged muscle pain is, in particular, likely toinduce central sensitization, because input from muscle nociceptors ismore effective in inducing prolonged changes in the behavior of dorsalhorn neurons than is input from cutaneous nociceptors (Wall and Woolf1984). Recent research from the present inventors does for the firsttime support that there is a clear relation between central painsensitivity and the increased muscle pain in patients with tension-typeheadache, and that the increased central pain sensitivity is induced bythe increased muscle pain. Thus, it has recently been demonstrated thatpatients with chronic tension-type headache have decreased painthresholds to various types of stimuli both at cephalic and atextra-cephalic locations (Bendtsen et al. 1996b), indicating a state ofcentral hypersensitivity, and that there is a significant correlationbetween, cephalic as well as extra-cephalic pain thresholds and thetotal pericranial tenderness recorded by manual palpation (Bendtsen etal. 1996a). These findings demonstrate that there is a closerelationship between the increased pericranial tenderness and thecentral hypersensitivity in chronic tension-type headache, but it doesnot reveal the cause and effect relationship between theseabnormalities. However, since it is known that patients with episodictension-type headache have normal pain thresholds (Jensen et al. 1993b)and that chronic tension-type headache usually evolves from the episodicform (Langemark et al. 1958), and since experimentally inducedtenderness of masticatory muscles precedes the induced headache byseveral hours in patients with tension-type headache (Jensen and Olesen1996), it is most likely that increased myofascial tenderness precedescentral hypersensitivity.

EXAMPLE 2

[0293] Mechanisms of Spontaneous Tension-Type Headaches.

[0294] An Analysis of Tenderness, Pain Thresholds and EMG

[0295] Pericranial muscle tenderness, EMG-levels and thermal andmechanical pain thresholds were studied in 28 patients with tension-typeheadache and in 30 healthy controls. Each patient was studied during aswell as outside a spontaneous episode of tension-type headache. Outsideof headache muscle tenderness and EMG-levels were significantlyincreased compared to values in controls subjects, while mechanical andthermal pain thresholds were largely normal. During headache muscletenderness evaluated by blinded manual palpation increasedsignificantly, while pressure pain thresholds remained normal andpressure pain tolerances decreased. Thermal pain detection and tolerancethreshold decreased significantly in the temporal region, but remainednormal in the hand. EMG-levels were unchanged during headache. Thefindings indicate that one of die primary sources of pain intension-type headache may be a local and reversible sensitization ofnociceptors in the pericranial muscles. In addition, a segmental centralsensitization may contribute to the pain in frequent sufferers oftension-type headache. The present study, for the first time, examinesthe same patients both during headache and outside of a headache episodewith the following tests: EMG, pericranial palpation, mechanical andthermal pain thresholds. The aim was to analyze the relative importanceof central and peripheral nociceptive factors.

[0296] Subjects and Methods

[0297] Subjects

[0298] Twenty eight patients, 11 males and 17 females, with frequentepisodic or chronic tension-type headache fulfilling the IHS-criteria(HCCIHS 1988) were included (Table IV). The patients were recruited fromthe out-patient headache clinic at Gentofte Hospital, Denmark. 9patients with frequent episodic tension-type headache (ETH)³ 8 days permonth and 19 patients with chronic, but not daily, tension-type headache(CTH) (HCCIHS 1988) were included. The reason for this selection wasthat patients had to have frequent headaches as well as frequent dayswithout headache in order to be studied in both states. Furtherinclusion criteria were frequent headaches during at least one year andan age between 18 and 70 years. The exclusion criteria were: Dailyheadache, migraine more than 1 day per month, cluster headache ortrigeminal neuralgia, other neurological, somatic or psychiatricdisorders, concurrent ingestion of major medications including migraineprophylactics, any form of drug abuse or dependency including largeamounts of plain analgesics. A diagnostic headache diary had to befilled out during a 4 week run-in period to ensure that patientsfulfilled the inclusion criteria. A complete physical and neurologicalexamination was performed before entry. Thirty age- and sex-matchedhealthy subjects without tension-type headache (<14 days TH/year) wereused as controls (Table IV). Informed consent vas obtained and the studywas approved by the local ethical committee.

[0299] Methods

[0300] The patients were examined randomly during and outside a typicalepisode of tension-tape headache. The intensity of the headache wasrecorded initially on a 100 mm Visual Analogue Scale (VAS), where 0indicated no pain at all and 100 mm indicated the worst imaginable pain.Examinations were separated by at least one week and performed at thesame time of the day in order to eliminate diurnal variations. Patientswere not allowed to take any medication on the days of examination.Healthy controls were investigated once.

[0301] Examination

[0302] The examination was performed in a standardized fashion by thesame investigator, a trained technician (LH), throughout the wholestudy. The technician was blinded to the subjects' headache history andpresence or absence of a possible muscular factor. Before measuring painthresholds each individual was carefully instructed to apply the sameinterpretation of ‘painfhl’ throughout the study. Initial test sessionswere applied to all subjects in order to familiarize them with the testconditions.

[0303] Palpation Method

[0304] Pericranial tenderness was evaluated by palpation of 9 pairs ofmuscles and tendon insertions in a standardized way. Each patient wasexamined by the technician and the physician in random order. Tendernesswas scored at each location according to a four point scale from 0 to 3,and scores from all sites were summated. The maximally possible scorewas thus 54 points. This Total Tenderness Score system (TTS) haspreviously proved to be reliable (Bendtsen et al. 1996).

[0305] Pressure Pain Threshold

[0306] The mechanical pain thresholds and tolerances were evaluatedbilaterally on the distal dorsal part of the second finger. Similarly, 2cranial locations, one with interposed muscle, the anterior part of thetemporal muscle (temp) and one without interposed muscle; the parietalregion (par) were examined (Petersen et al. 1992). A standardized andpreviously evaluated method was applied using an electronic pressurealgometer (Somedic AB, Sweden) with a 0.79 cm. circular probe (Jensen etal. 1986, Brennum et al. 1989). The Pressure Pain Detection Threshold(PPDT) was defined as the threshold, where the pressure sensation becamepainful, whereas the Pressure Pain Tolerance (PPTO) was the thresholdwhere the patient would no longer tolerate the pain (Petersen et al.1992). By pressing a hand-held button the subjects indicated that thepain threshold was reached and the pressure was immediately released. Ifpatients did not activate the button, the experiment was terminated whenreaching 800 kPa in the cranial region and 1500 kPa in the fingers. Eachthreshold was calculated as the median value of 3 consecutiverecordings.

[0307] Thermal Thresholds

[0308] Thermal thresholds were evaluated with a computerized version ofthe Thermotest (Somedic AB, Sweden) (Fruhstorfer et al. 1976). Thethermode consisted of series-coupled Peltier elements and measured 25×50mm. Two locations, the thenar region of the hand and the anterior partof the temple were examined bilaterally. Three parameters were recordedin each region i.e. the Warm Detection (WD) defined as the lowesttemperature detected as warm, the Heat Pain Detection (HPD) defined asthe temperature where the heat sensation became painful, and the HeatPain Tolerance (HPTO) defined as the highest temperature tolerated(Langemark et al. 1989, Jamal et al. 1985). A baseline temperature of32° C. and a 1.0° C./sec rate of temperature change was used (Langemarket al. 1989). Heat stimulation was terminated when reaching 52° C. ifthe patients had not responded before. By pressing a hand-held buttonthe subjects indicated, when the thresholds were reached. The thermodewas immediately removed from the area, the exact value was recorded inthe computer and the stimulator returned to baseline. Each threshold wascalculated as the average of 5 determinations performed with intervalsof 10-15 seconds.

[0309] Electromyography

[0310] A standardized, preciously described method was used (Jensen etal. 1993a, Jensen et al. 1994). The EMG signals from the temporal andtrapezius muscles were recorded bilaterally using a 4-channelselectromyograph (Counterpoint, Dantec, Copenhagen). Data were collectedduring 2 conditions i.e. resting in the supine position in 20 one secondperiods interrupted by 5 second interval and during maximal voluntarycontraction (MVC). The MVC lasted a maximum of 5 seconds and wasrepeated 5-6 times with 30 second intervals. MVC recording sessionslasting one second were analyzed and the highest value of Root MeanSquare (RMS) of the EMG was selected (Jensen et al. 1993a, Jensen et al.1994). The power spectrum of each of the 1 second measurement sessionswas calculated for the frequency range 0 to 1 kHz and Mean Frequency wasextracted (Jensen et al. 1993a).

[0311] Statistics

[0312] Wilcoxons rank sum test (Wilc.) was used to compare paired datafrom headache subjects. Mann-Whitneys test (M-W.) was used to comparedata between controls and patients. Mean values of right and left sidedobservations are presented. Five percent level of significance was used.

[0313] Results

[0314] Subjects

[0315] All the included patients and healthy controls completed thestudy. There were no significant differences in age and sex-distributionbetween healthy subjects and patients (Table IV).

[0316] Headache

[0317] The headaches examined fulfilled the diagnostic criteria fortension-type headache (HCCIHS 1988). Seventy one percent (20/28) had abilateral headache, whereas 29% (8/28) had a unilateral headache. Themedian VAS score was initially 35 mm (range 17-75 mm).

[0318] Variation between Observers

[0319] The Total Tenderness Scores (TTS) as recorded by the 2 observers(LH, RJ) at the initial examination were comparable in patients (Wilc.p=0.38) and in healthy controls (Wilc. p=0.27).

[0320] Side to Side Relation

[0321] The side to side variations were tested in patients as well as incontrols, and results corresponded to previous methodological studies(Petersen et al. 1992, Jensen et al. 1986, Jamal et al. 1985, Jensen etal. 1993a).

[0322] Relation between controls and patients free of headache

[0323] Tenderness

[0324] Median TTS in TH patients free of headache was 13 andsignificantly higher than 4 in healthy controls (M-W.p<10⁻⁵) (FIG. 5).

[0325] Pressure Pain Thresholds

[0326] Pressure Pain Detection Thresholds and Pain Tolerance Thresholdsin patients were not significantly different from those in healthycontrols in any of the examined regions (Table V).

[0327] Thermal Thresholds

[0328] The warm detection threshold, the heat pain detection andtolerance thresholds in the hands did not differ between patients andcontrols. In the temporal regions of headache free patients the warmdetection (WD) and heat pain thresholds (HPD) were increased compared tohealthy controls (Table VI) (M-W, WD:p<0.001; HPD:p=0.047). The heatpain tolerances were similar in the 2 groups (Table VI).

[0329] EMG

[0330] During rest amplitude-levels were higher in patients in theheadache free condition as compared to healthy controls (M-W.m.temp:p<0.001; m.trap p=0.016). No other significant differences ortendencies were detected (Table VII).

[0331] Relation to the Headache State

[0332] Tenderness

[0333] The total tenderness score increased from 13 (range 0-29) outsideof headache to 16 (range 1-34) during headache (Wilc.p<0.01) (FIG. 5)

[0334] Pressure Pain Thresholds

[0335] No significant differences in pressure pain detection thresholdswere found when results during headache were compared to the headachefree condition. Pressure pain tolerances in the parietal regionsdecreased significantly during the headache (Wilc. p=0.03), whereas thepressure pain tolerances from other locations were unaffected (FIG. 6).

[0336] Thermal Thresholds

[0337] Heat pain detection (Wilc.p=0.011) and tolerances (Wilc.p=0.016)were lower in the temporal region during headache as compared to theheadache free condition. No differences were seen in the hand (FIG. 7).

[0338] EMG

[0339] No significant variations appeared when EMG parameters during theheadache episode were compared to the headache free condition (FIGS.8A+B).

[0340] Discussion

[0341] Comparison of Headache-Free Patients and Control Subjects

[0342] Myofascial tissue has been considered an important source ofnociception in tension-type headache by some investigators (Travell etal. 1983, Drummond et al. 1987), whereas others favor alterations incentral pain processing resulting in a state of hypersensitivity toincoming stimuli from myofascial and other cephalic tissues (Schoenen etal. 1991a, Schoenen et al. 1991b). Previous findings of increasedcranial and peripheral sensitivity in patients with chronic tension-typeheadache support such central mechanisms (Langemark et al. 1989,Schoenen et al. 1991b). However, normal cranial pressure pain thresholdshave recently been described in subjects with chronic tension-typeheadache from a general population (Jensen et al. 1993b) and in patientspith episodic tension-type headache from headache clinics (Goebel et al.1992. Eovim et al. 1992). Comparing groups of headache patients tonormal controls involves many confounding factors. These are greatlydiminished in studies comparing the headache state and the non-headachestate in the same individuals. The same patients were studied bothduring and outside of headache. The headache mechanisms were analyzed bymeans of EMG, pericranial palpation, thermal and mechanical painsensitivity.

[0343] The present study confirms that pericranial muscles of thesepatients outside of headache are more tender than in healthy subjects(Jensen et al. 1993, Hatch et al. 1992, Langemark et al. 1987). Moreimportantly it is demonstrated, for the first time, that tendernessincreases during the headache phase. Are these findings due to centralor peripheral hypersensitivity? Normal pressure pain thresholds andpressure pain tolerances outside headache both in the cranial region andin the hands indicates that central pain perception is not generallyaffected in these patients. The warm detection and heat pain detectionthresholds were increased, not decreased, in the temporal region andnormal in the hands. Thus, decreased sensitivity to noxious heat can bedue to either a local factor in the skin which decreases the cutaneousreceptor sensitivity or central factors inhibiting the incoming stimuli.No studies have addressed this issue before and the finding needsfurther clarification. Higher EMG-amplitude values during rest wererecorded in headache free patients as compared to normal controls. Thesefindings correspond with a recent population study where amplitudelevels from the temporal and the frontal muscles were increased insubjects pith chronic tension-type headache (Jensen et al. 1994). Thesefindings indicate that the muscles are insufficiently relaxed. Whetherthis is causative or secondary to the headache has been much debated,but lack of correlation to the pain state (see below) indicates that itmay be a secondary characteristic. In the study presented in example 3it is described that sustained tooth clenching may be an initiatingevent of tension-type headache, but the present results suggests thatother mechanisms are responsible for maintaining it.

[0344] Relation to the Headache State

[0345] During headache pericranial tenderness increased, indicatingperipheral or central sensitization of myofascial nociception (Jensen etal 1990). EMG-levels were unchanged during headache which makes itunlikely that pain elicited activity in pericranial muscles can explainthe increased tenderness. Pressure pain thresholds were unaffected bythe headache state whereas thermal pain detection and tolerancethresholds decreased selectively in the temporal region indicating thatthe actual headache episode may be associated with a segmental centralsensitization and/or a decreased antinociception. A more generallydefective central pain modulation, as previously suggested (Schoenen eta. 1991a), is less likely, because pressure pain thresholds andtolerances in the hands were completely normal. A possible segmentaldisturbance at the spinal/trigeminal level may be transient andreversible since pain tolerances were normal outside of headache. Theresults are thus in line pith the recent experimental studies by Hu etal. (Hu et al. 1992). In these important studies deep craniofacialmuscle afferents were stimulated and prolonged facilitators effects inthe trigeminal nociceptive brain-stem neurons of anaesthetized rats wereinduced. These findings were supported by the recent findings thatexperimental myositis induces functional reorganization of the ratdorsal horn (Hoheisel et al. 1994). A reversible expansion of thecutaneous mechanoreceptive field was noted by Hu et al. and thespontaneous activity in cutaneous afferents was increased (Hu et al.1992) in correspondence with previous studies (Coderre et al. 1993,Heppelmann et al. 1987). It is also known that input from deepmyofascial tissue is more effective in inducing central sensitizationthan cutaneous input (Wall et al. 1984, Yu et al. 1993).

[0346] The decreased pain tolerance during headache in the present studymay indicate a central hyperalgesia. As pain tolerances were normaloutside of headache, the central changes are probably reversibly linkedto the headache pain in the episodic form, whereas a more frequentactivation may induce a permanent pain condition, i.e. the chronic form.The cascade of increased nociceptive activity from deep myofascialtissues may induce secondary changes such as plasticity andsensitization in the spinal dorsal horn/trigeminal nucleus (Hu et al.1992, Hogeisel et al. 1994, Coderre et al. 1993, Heppelmaan et al.1987). The central nociceptive modulation and perception are therebydisturbed resulting in a prolonged hyperalgesia, which may persistdespite disappearance of the peripheral noxious stimulus. When thecentral sensitization becomes sufficiently strong and widespread, theheadache becomes chronic due to self perpetuating disturbances in thepain perception system.

[0347] Many of the abnormal findings in previous series of severelyaffected patients with chronic tension-type headache (Schoenen et al.1991a, Langemark et al. 1989, Schoenen et al. 1991b) maybe a function ofthe pain rather than the initial causative factor. It can therefore berecommended to study mechanisms in patients with episodic tension-typeheadache. Studies comparing the pain state to the pain free state inthese patients are likely to be the most informative. TABLE IV Clinicalcharacteristics of the subjects studied TH patients Controls Number (n)28 30 Males 11 12 Females 17 18 Age(years) 45(28-63) 42(23-67) Yearswith TH 23(1-45) — Frequency of TH 20(8-27) — days/28 days Frequency ofmigr  8(2-11) — days/year (n = 14)

[0348] TABLE V Pressure pain thresholds in 28 headache patients free ofheadache and 30 healthy controls. Mean values of left and right side aregiven in kPa with SD in brackets. Pressure pain Pressure pain detectiontolerance patients 384(161) 739(271) HANDS controls 358(168) 785(289)patients 225(97) 366(141) TEMPORAL REG. controls 203(103) 387(157)patients 339(172) 560(179) PARIETAL REG. controls 317(194) 571(201)

[0349] TABLE VI Thermal thresholds in 28 headache patients free ofheadache and 30 healthy controls. Mean values of left and right side aregiven in ° C. with SD in brackets. Warm Detection Pain threshold Paintolerance patients   34.3 (3.1)  42.3 (3.1) 47.0 (2.2) HANDS controls  34.4 (1.2)  42.4 (2.7) 47.5 (2.2) patients ***34.7 (1.6) *40.1 (2.8)44.1 (2.0) TEMP controls   33.8 (0.8)  39.1 (2.7) 43.9 (8.5)

[0350] TABLE VII EMG levels in 28 patients free of headache and in 30healthy controls. REST indicate resting conditions and MVC indicatemaximal voluntary contraction. Mean values of left and right side aregiven with SD in brackets. REST MVC RMS Mean F RMS Mean F (uV) (Hz) (uV)(Hz) TEMPORAL MUSCLES patients **3.1 (2.4) 81 (25) 164 (66) 173 (28)controls  2.3 (0.9) 74 (17) 181 (101) 155 (30) TRAPEZIUS MUSCLESpatients  *3.6 (1.2) 40 (10) 260 (141)  88 (18) controls  3.1 (0.9) 41(9) 259 (131)  88 (16)

EXAMPLE 3

[0351] Intiating Mechanisms of Experimentally Induced Tension-TypeHeadache

[0352] To elucidate possible myofascial mechanisms of tension-tapeheadache, the effect of 30 minutes of sustained tooth clenching (10% ofmaximal EMG-signal) was studied in 58 patients with tension-typeheadache and in 30 age and sex matched controls. Pericranial tenderness,mechanical and thermal pain detection and tolerance thresholds and EMGlevels were recorded before and after the clenching procedure. Within 24hours 69% of patients and 17% of controls developed a tension-tapeheadache. Shortly after clenching, tenderness was increased in the groupwho subsequently developed headache, whereas tenderness was stable inthe group of patients who remained headache free. Mechanical painthresholds evaluated by pressure algometry remained unchanged in thegroup which developed headache, whereas thresholds increased in thegroup which did not develop headache. Thermal pain detection andtolerance thresholds remained unchanged in both groups. These findingsindicate that, although there may be several different mechanisms oftension-type headache, one of them is sustained muscle contraction. Aperipheral mechanism of tension-type headache is therefore possible,whereas a secondary segmental central sensitization seems to be involvedin subjects with frequent tension-type headache. Finally, the increasein pressure pain thresholds in patients who did not develop headachesuggest that clenching activated their antinociceptive system whereasthose developing headache were unable to do so.

[0353] Introduction

[0354] Tension-type headache is extremely prevalent (Rasmussen et al.1991) and represents a major health problem (Rasmussen et al. 1992).Nevertheless, its pathogenic mechanisms are largely unknown (Pikoff etal. 1984, Olesen et al. 1991). Sustained involuntary muscle contractionhas been suggested as an important source of pain in tension-typeheadache (Travell et al. 1983). In recent years, central mechanisms havehowever, been favoured (Schoenen et al. 1991a). Substantial evidence forany of the suggested pathogenetic mechanisms has not yet been available.To study the initiating mechanisms of headache it is valuable to induceit. The time necessary to reach the laboratory males it impossible tostudy the initial phase of spontaneous attacks. Furthermore, using aknown stimulus to induce headache makes it easier to analyze itsmechanisms. Experimental tooth clenching has previously induced mildheadaches in migraineurs (Jensen et al. 1985) but has never been studiedin subjects with tension-type headache. In the present studytension-type headache was induced by sustained muscle contraction inpatients and controls and studied the pre- and post-contraction phase bymeans of EMG, thermal and pressure pain thresholds as well as headacheand tenderness scoring.

[0355] Subjects and Methods

[0356] Subjects

[0357] Fifty-eight patients with frequent episodic or chronictension-type headache fulfilling the IHS-criteria (HCCIHS 1988) wereincluded (Table VIII). Twenty eight patients had frequent episodictension-type headache 38 days with headache per month and 30 patientshad chronic, but not daily, tension-type headache (HCCIHS 1988). Thereason for this selection was that patients had to have frequentheadaches as well as days without headache in order to be studied in thelatter state. Further inclusion criteria were duration of frequenttension-type headache in at least one year and age between 18 and 70years. The exclusion criteria were: daily headache, migraine more than 1day per month, cluster headache, trigeminal neuralgia, otherneurological, systemic or psychiatric disorders, ingestion of majormedications including migraine prophylactics, any form of drug abuse ordependency as daily ergotamine or large amounts of plain analgesics. Thepatients were recruited from the out-patient headache clinic at GentoftcHospital and complete physical and neurological examinations were donebefore entry. Thirty healthy age- and sex matched subjects (headache <14days/year) were used as controls (Table VIII). Informed consent wasobtained and the study was approved by the local ethical committee.

[0358] Procedure

[0359] All patients had to fill in a diagnostic headache diary during a4 week run-in period to ensure that patients fulfilled the inclusioncriteria. All subjects, patients and controls, were told to fill out aspecial diary for at least 24 hours after the study. Patients wereexamined when free of headache and were not allowed to have taken anyanalgesics on the day of examination. The EMG-parameters and paincharacteristics were recorded twice on the day of examination,immediately before and after the clenching procedure. A 100 mm VisualAnalogue Scale (VAS), where 0 mm was no pain at all and 100 mm was theworst imaginable pain was used. Recordings of pain intensity were madebefore, 30, 60 and 90 minutes after the clenching procedure in thelaboratory, as well as after 4, 6, and 24 hours after the clenching inthe diary. All subjects were informed that the purpose of the study wasto measure variations in muscle tension and pain characteristics duringtooth clenching. They were not informed of the risk of developingheadache in order to avoid bias.

[0360] Examination

[0361] The examination was performed in a standardized way by the sameperson, a trained technician, throughout the whole study. The study wasblinded as the technician was unaware of the subjects headache history.Before recordings of pain thresholds each individual was carefullyinstructed to apply the same interpretation of ‘painfiul’ throughout thestudy. Initial test sessions were applied to all subjects in order tofamiliarize them with the test conditions.

[0362] Palpation

[0363] Pericranial tenderness was evaluated by palpation of 9 pairs ofmuscles and tendon insertions by the technician and the physician in astandardized, randomized procedure. Tenderness was scored in eachlocation according to an ordinal scale from 0 to 3, and scores from allsites were summated. The maximum possible score was thus 54 points. ThisTotal Tenderness Score system (TTS) has previous proved to be reliable(Bendtsen et al. 1995).

[0364] Pressure Pain Thresholds

[0365] The pressure pain thresholds were evaluated bilaterally on thedistal dorsal part of the second finger, and in two cranial locations,one with interposed temporal muscle (Temp) and one without interposedmuscle, the parietal region (Par). A standardized and previouslyevaluated method vas applied using an electronic pressure algometer(Somedic AB, Sweden) with an 0.79 cm² circular stimulation probe(Petersen et al. 1992, Jensen et al. 1986, Brennum et al. 1989). Twopain qualities were recorded, the Pressure Pain Detection Threshold(PPDT) defined as the threshold, where the pressure sensation becamepainful, and the Pressure Pain Tolerance (PPTO) defined as the thresholdwhere the patient would no longer tolerate the pain (Petersen et al.1992). By pressing a hand held button the subjects indicated that thethreshold was reached, and the pressure was released immediately. Ifpatients did not activate the button, the experiment was terminated whenreaching 800 kPa in the cranial region and 1500 kPa in the fingers. Eachthreshold was calculated as the median value of 3 determinationsperformed with intervals of 10-15 seconds.

[0366] Thermal Pain Thresholds

[0367] Thermal thresholds were evaluated with a computerized version ofthe Thermotest (Somedic AB, Sweden) (Fruhstorfer et al. 1976). Thethermode consisted of series-coupled Peltier elements and measured 25×50mm. The thenar region of the hand and the anterior part of the temporalregion were examined bilaterally. Three stimulation qualities wererecorded: the Warm Detection limit (WD) defined as the lowesttemperature detected as warm, the Heat Pain Detection (HPD) defined asthe temperature where the heat sensation became painful, and the HeatPain Tolerance (HPTO) defined as the highest temperature tolerated(Jamal et al. 1985). A baseline temperature of 32° C. and a 1.0° C./secrate of temperature change was used. Heat stimulation was terminatedwhen reaching 52° C., if the patients had not responded before. Bypressing a hand-held button the subjects indicated when the actualthreshold vas reached. This value was recorded automatically and thestimulator returned to baseline. Each threshold was calculated as theaverage of 5 determinations performed with intervals of 10-15 seconds.

[0368] Electromyography

[0369] EMG signals from the temporal and trapezius muscles were recordedbilaterally by a 4-channels electromyograph (Counterpoint, Dantec,Copenhagen) (Jensen et al. 1993a). A standardized, previously describedmethod where the temporal and frontal muscles were investigated wereapplied (Jensen et al. 1993a). Data were collected during rest in thesupine position and during maximal voluntary contractions (MVC) (Jensenet al. 1993a). The RMS voltage was measured. Power spectrum wascalculated for the frequency range 0 to 1 kHz and Mean Frequencies (MeanF) were extracted (Jensen et al. 1993a).

[0370] Provocation

[0371] After the initial recording series the subjects were instructedto clench their molar teeth and the EMG activity from the temporalmuscles was recorded. The subjects were instructed to clench their teethat 10% of their individual MVC value and to keep this value constant for30 minutes. The subjects received visual feed back from the EMG-monitor,and were allowed 3 short (<60 sec) rests during the session. Force wasnot measured.

[0372] Statistics

[0373] The chi square test was used to test differences in headachecharacteristics between patients and controls. The sign test was used tocompare the frequency of provoked headache with the expected frequency.Wilcoxon's rank sum test (Wilc.) was used for comparing paired datawithin subjects, and Mann-Whitney's test (M-W.) was used for comparingunpaired data between patients and controls. Five percent level ofsignificance was used.

[0374] Results

[0375] All the included patients and healthy controls completed thestudy. No significant variation in age- and sex distribution betweenpatients and controls appeared (Table VIII). Only two left handedsubjects (1 patient, 1 control) were included. Therefore no correctionfor hand dominance was made.

[0376] Development of Headache

[0377] In total, 69% (40/58) of the patients and 17% (5/30) of thehealthy controls developed headache within 24 hours after toothclenching. The frequency of headache among patients was significantlyhigher than expected from their usual headache frequency (p=0.016) andhigher than in healthy controls (p<0.0001). Twenty-eight percent ofpatients (16/58) and 7% of controls (2/30) developed headache within thefirst hour after tooth clenching. The median duration from clenching todevelopment of headache was 1.5 hours in patients (range 0.5-20 hours)and 1.5 hours (range 0.5-6 hours) in controls. All headaches, inpatients as well as in controls, fulfilled the diagnostic criteria fortension-type headache (n=7). The headaches were bilaterally located in85% (34/40) of the patients and in all controls. It was of pressingquality in all subjects. It was not aggravated by physical activity in85% (34/40) of the patients and in all the controls. No associatedsymptoms such as nausea, photophobia or phonophobia were reported.Initially, the headache was cry mild in both groups, but the intensityincreased during the following hours in patients (FIG. 9). Four and 24hours after clenching those patients who bad developed headache hadsignificantly higher mean VAS-scores than those few healthy controls whohad developed headache (M-W. p=0.02) (FIG. 9). In patients, the medianheadache duration was 8 hours (range 1-24 hours) but not significantlydifferent from 3 hours (range 2-24 hours) (M-W. p=0.10) in the smallnumber of controls (n=5) with headache.

[0378] Variation between Observers

[0379] The Total Tenderness Scores (TTS) recorded by the 2 observers atthe initial examination did not differ significantly within patients(Wilc. p=0.24) nor in healthy controls (Wilc. p=0.27).

[0380] Variation between Left and Right Sided Observations

[0381] The side to side variations were tested in patients as well as incontrols, and results corresponded to previous methodological studies(Petersen et al. 1992, Fruhstorfer et al. 1976, Jensen et al. 1993a,Jensen et al. 1993b). For simplicity mean values of left and right sidedobservations are presented in the following.

[0382] Relation between Measurements in Patients and Controls beforeClenching

[0383] Tenderness

[0384] Initial median TTS in patients was 12 (range 0-29) andsignificantly higher than the median score of 4 (range 0-10) in healthycontrols (M-W.p<10⁻⁷).

[0385] Pressure Pain Thresholds

[0386] Pressure Pain Detection Thresholds were increased in the temporalregions of headache patients compared with healthy controls(M-kV.p=0.03) (Table IX). No significant variations or tendencies werefound in the other locations (M-W.fingers p=0.98; parietal p=0.21)(Table IX).

[0387] Pressure Pain Tolerances in patients were not significantlydifferent from those in healthy controls in any of the examined regions(M-W.fingers p=0.87, temp. p=0.45; parietal p=0.69) (Table IX).

[0388] Thermal Thresholds

[0389] The warn detection threshold was higher in the temporal regionsin patients than in healthy controls (M-W. p=0.02), while the warmdetection in the hands was normal (M-W. p=0.26) (Table X). The heat paindetection and tolerance thresholds were normal in both locations (TableX).

[0390] EMG

[0391] During rest the EMG-amplitude was significantly increased in thetrapezius muscle of patients compared to controls (M-W.

[0392] Trap p=0.04). A similar but not quite significant increase wasseen in the temporal muscles (M-W.Temp p=0.10) (Table XI). Frequencyvalues during rest as well as all EMG values during MVC were notdifferent from those of controls (Table XI).

[0393] Effect of Clenching on the Measured Tests

[0394] Tenderness

[0395] The median initial TTS was 12 (range 0-28) in patients whodeveloped headache and was increased significantly to 14 (range 0-33) atthe recording 90 minutes after clenching (Wilc.p<0.001) (FIG. 10). Themedian TTS in patients who remained headache free was also 12 (range0-24) and remained 12 (range 033) after clenching (Wilc.p=0.33). Amarked, but not quite significant increase in TTS from 6 to 10 was seenin the few control subjects who developed headache (Wilc.p=0.06),whereas TTS only increased from 4 to 5 in controls who remained headachefree (Wilc.p=0.0015) (FIG. 10).

[0396] Pressure Pain Thresholds

[0397] Pressure Pain Detection Thresholds in fingers and in the temporalregions remained constant in those subjects (patients as well ascontrols) who developed headache, whereas a significant increase of paindetection thresholds was seen in subjects who did not develop headache(Wilc. Patients fingers p=0.01; temp p=0.024; Controls fingers p=0.04;temp p=0.01) (FIG. 11A).

[0398] Pressure Pain Tolerance decreased in the parietal region inpatients who developed headache after clenching (Wilc.p=0.009), whereasthe tolerances remained stable in patients who remained headache free.Pressure Pain Tolerances in the same region increased in controls whoremained headache free after stimulation (Wilc.p=0.003) (FIG. 11B).Pressure Pain Tolerance was stable in the hand and the temporal regionin all subjects without regard to headache development (FIG. 11B).

[0399] Thermal Thresholds

[0400] In patients as well as in controls, no significant differences inthermal thresholds were seen between those who developed headache andthose who did not (FIG. 12).

[0401] EMG

[0402] During resting condition a significant decrease in amplitudevalue was seen the temporal and the trapezius muscles after clenchingboth in patients (Wilc.Temp. p<0.001, Trap. p<0.01) and in controls(Wilc. Temp.p<0.001, Trap. p<0.01). This decrease was similar in thosewho developed headache and in those who did not (FIG. 13A). In contrast,only the group of patients who developed headache showed decreasedamplitude values in the temporal muscle during MVC (Wilc. p=0.011) (FIG.13B).

[0403] Discussion

[0404] Studies in a general population and in specialized headacheclinics have revealed that increased muscle tenderness and frequenttooth clenching are consistent findings in subjects with tension-typeheadache (Jensen et al. 1993b, Jensen et al. in prep., Wanmann et al.1986, Langemark et al. 1987, Lous et al. 1982). Whether these relationsare causal or secondary to the pain has not yet been clarified. However,if there is a causal connection it should be possible to create anexperimental headache model by interfering smith these systems. Althoughseveral attempts to make experimental pain in the chewing muscles havebeen made (Christensen et a. 1981, Clark et al. 1991, Bakke et al.1989), only few studies have focused specifically on headache (Jensen etal. 1985, Magnusson et al. 1984). Jensen et al. reported that 54% of 48migraineurs developed a muscle-contraction like headache aftershortlasting sustained clenching (Jensen et al. 1985). These findingsindicate that headache subjects in general are more susceptible todevelop headache after sustained muscle contraction.

[0405] Relation between Measurements in Patients and Controls beforeClenching

[0406] Tenderness

[0407] The finding of increased muscle tenderness by manual palpation asthe most significant difference between headache patients and healthycontrols supports previous findings in a general population (Jensen etal. 1993b). When selecting psycho-physiological measures it is importantto consider the information carried by the particular measure. Localtenderness as recorded by manual palpation is assumed to indicateincreased nociception from the free nerve endings in the connectivetissue of muscles, fascia and tendons (Jensen et al. 1990, Torebjork etal. 1984). Such increased nociception is probably due to a sensitizationof nociceptors by bradykinin, prostaglandines, substance P, 5-HT,histamine and potassiu (Mense et al. 1992, Jensen et al. 1992). Reducedmuscle blood flow leading to ischemia has been suggested as the cause oftenderness (Myers et al. 1983), but recently normal blood flow in thetemporal muscles of patients with chronic tension-type headache has beendemonstrated (Langemark et al. 1990).

[0408] Pressure Pain Thresholds

[0409] A decreased pressure pain detection threshold indicates a stateof allodynia, i.e. pain elicited by stimuli which normally arenon-noxious. A decrease in pressure pain tolerance threshold indicates astate of hyperalgesia, i.e. increased sensitivity for supra thresholdnoxious stimuli, which may and ray not coexist with allodynia (Jensen etal. 1990). Identification of allodynia and hyperalgesia may therefore beof special interest in the study of central and peripheral mechanisms ofnociception. In addition, we have studied responses from the hands andthe cranial regions in order to determine a possible anatomicalvariation in the response to pain stimulation. We also waited to studythe muscular contribution and recorded thresholds from two neighboringcranial regions one with and one without interposed muscle. The factthat pressure pain detection thresholds and tolerances were lower in thetemporal region than in the nearby parietal region indicates thatmyofascial nociception contributes considerably to the recordedresponses. However, the finding of largely normal thresholds andtolerances in headache free patients indicates that the general painsensitivity in the cranial region is not permanently disturbed aspreviously suggested (Schoen et al. 1991a, Langemark et al. 1989).

[0410] Thermal Thresholds

[0411] Thermal warm detection represents the activity in unmyelinatedC-fibers (Campbell et al. 1989) whereas the heat pain detectionrepresents activation of cutaneous C-fibers responsive to mechanical andheat stimuli and their central modulation (Campbell et al. 1909). Inaddition, the myelinated A mechano beat fibers type I may be activatedwhen the heat pain tolerance is tested. If central pain perception isincreased, decreased warmth and heat pain thresholds are expected.However, thermal pain detection and tolerances were normal in theheadache patients suggesting normal pain sensitivity as discussed above.The present findings differ from a previous finding of decreased heatpain detection thresholds in patients with chronic tension-type headache(Langemark et al. 1989). In the prior study patients were, however, moreseverely affected and most of them had daily headaches and long lastingdrug overuse (Langemark et al. 1989). It is likely that chronic pain mayinduce central sensitization to incoming nociceptive signals, and thepreviously described decrease in noxious thresholds in severely affectedheadache patients may, therefore, be an effect of chronic pain ratherthan its cause.

[0412] EMG

[0413] It has been a widely held view that tension-type headache iscaused by involuntary contraction of cranial muscles. The slightlyincreased amplitude values during rest indicate that the pericranialmuscles arc insufficiently relaxed (Jensen et al. 1994). However, thisincrease in EMG level was unaffected by the presence or absence ofheadache, and is therefore not likely to be a primary cause of pain(Jensen et al. 1994). The decreased amplitude values during maximalvoluntary contraction in patients developing headache and not incontrols indicate that in some other way a muscular factor may beinvolved (Jensen et al. 1994).

[0414] Effect of Clenching on Headache and the Measured Tests

[0415] The present results indicate that sustained muscle contractioncan induce headache although the recordings have not been repeatedduring a similar placebo provocation. An important finding is theincreased tenderness in subjects who developed headache. Headache hadnot developed in the majority of subjects at 90 minutes afterprovocation, when the increased tenderness was recorded. This suggeststhat clenching causes tenderness, that tenderness precedes headache andthat tenderness may be one of the causes of the subsequent headache. Asimilar increase in tenderness scores during spontaneous attacks oftension-type headache has recently been shown (Jensen et al. in press).Muscle tenderness usually requires several hours to develop (Christensenet al. 1981). A further increase in tenderness would therefore probablyhave been detected if we had continued to record tenderness severalhours after clenching. In the present study, the experimental headacheoccurred swish a lag time of one to several hours. In addition, the painwas mild initially and gradually, in the course of hours, reached itspeak. In contrast, the intensity of headache in control subjects did notincrease after onset. The very low VAS-score in controls may representdiscomfort rather than clinical relevant pain as reported by thepatients. This indicates that the antinociceptive system may bedeficient in headache patients. The exact degree of clenching seems tobe of minor importance. Approximately the same percentage of subjectsdeveloped headache with 10% of mammal contraction in the present studyand with 5% or 30% of maximal contraction in the previous migraine study(Jensen et al. 1985).

[0416] Mechanisms of Tension-Type Headache Suggested by the PresentResults

[0417] The pressure pain detection thresholds remained stable inpatients who developed headache but increased in subjects who did notdevelop headache. We also found decreased pain tolerances in patientswho developed headache, unchanged values in the remaining patients andincreased values in controls, suggesting that headache patients do notactivate their antinociceptive system or that it is less effective inthese patients (Le Bars et al. 1979). On the other hand, their centralantinociceptive suppression is not so permanently and severely affectedthat it is reflected in permanent hyperalgesia, since the noxiousthresholds and tolerances were normal outside of a headache episode. Inaddition, as the thermal thresholds remained unaffected of the headachestate, no evidence for a general hypersensitivity to pain was found. Thesimilar decreases in EMG-levels in both groups after clenching indicatethat the increased EMG-levels in patients free of headache may be asecondary characteristic. This is supported by similar findings in arecent study of patients during and outside of spontaneous tension-typeheadache attacks (Jensen et al. in press). Based on the presentfindings, results from previous studies (Jensen et al. 1993b, Jensen etal. 1994, Jensen et al. in press) mid results from recent animal studies(Mense et al. 1993, Le Bars et al. 1919) on peripheral and central painmechanisms we suggest the following mechanism of tension-type headache:involuntary contraction of muscles, due to mechanical or psychologicalstress, causes activation and chemical sensitization of the myofascialmechano receptors and their afferent fibres. This increased peripheralinput may result in sensitization and functional reorganization ofsecond order sensory neurons in the dorsal horn (Hoheisel et al. 1994)as stimuli in the deep myofascial tissues are much more effective, inthis respect than stimuli in the cutaneous tissues (Wall et al. 1984, Yuet al. 1993). Normally, increased peripheral nociceptive input iscounteracted by increased activity in the antinociceptive system and noheadache arises. However, in some individuals and under certaincircumstances this homeostatic mechanism does not function. An abnormalsensitization arises and combined with an impaired centralantinociceptive mechanism, an episode of tension-type headache maydevelop. However, the relative importance of peripheral and centralsensitization and of the antinociceptive system remain furtherclucidation. In conclusion, the results obtained be the presentinventors suggest that muscular factors play an important role in theinitiation of a headache episode. However, the further development andtransition into the chronic pain state is probably due to a centralsensitization with or without impairment of the central antinociceptivesystem. TABLE VIII Clinical characteristics of the subjects studied THpatients Controls Number (n) 58 30 Males 22 12 Females 36 18 Age(years)45(21-63) 42(23-67) Years with TH 23(1-45) — Frequency of TH 17(8-27) —days/28 days Frequency of migraine  7(2-12) — days/year (n = 28)

[0418] TABLE IX Pressure pain detection thresholds (PPDT) and tolerances(PPTO) in 58 headache patients free of headache and 30 healthy controls.Mean values of left and right side with SD in brackets are given in kPa.PPDT PPTO FINGER patients  353(137) 779(294) controls  358(168) 785(289)TEMPORAL REGION patients *220(76) 399(146) controls  203(103) 387(157)PARIETAL REGION patients  323(146) 600(190) controls  317(195) 571(201)

[0419] TABLE X Thermal thresholds in 58 headache patients free ofheadache and in 30 healthy controls. Mean values of left and right sidewith SD in brackets are given in ° C. Warm Pain Pain detection thresholdtolerance HANDS patients  34.5(1.2) 42.3(3.0) 47.2(2.3) controls 34.4(1.2) 42.4(2.7) 47.5(2.2) TEMPORAL REGION patients *34.2(1.7)39.6(2.7) 44.0(2.0) controls  33.8(0.8) 39.1(2.7) 43.9(2.9)

[0420] TABLE XI EMG levels in 58 patients free of headache and in 30healthy controls during rest and maximal voluntary contraction(MVC).Mean values of left and right side with SD in brackets are given; RMSindicate root mean square values of amplitudes (uV) and Mean F indicatemean frequency (Hz). REST MVC RMS Mean F RMS Mean F TEMPORAL MUSCLESpatients  2.7 (1.9) 78 (22) 164 (81) 164 (32) controls  2.3 (0.9) 74(17) 181 (101) 155 (30) TRAPEZIUS MUSCLES patients *3.5 (1.2) 39 (9) 246(124)  88 (16) controls  3.1 (0.9) 40 (9) 259 (131)  88 (16)

EXAMPLE 4

[0421] A Nitric Oxide Synthase Inhibitor is Effective in ChronicTension-Type Headache and is Counteracting Central Sensitization

[0422] Introduction

[0423] Nitric oxide (NO) is an almost ubiquitous molecule that probablyplans an important role in the modulation and transmission of pain(Meller and Gebhart 1993). NO is assumed to be of particular importancefor the development of central sensitization, i.e. increasedexcitability of neurons in the central nervous system (McMahon et al.1993; Meller and Gebhart 1993). In this way NO may contribute to thedevelopment of chronic pain The synthesis of NO is catalyzed by theenzyme NO synthase (NOS) (Moncada et al. 1991), Recent animal studieshave shown that NOS inhibitors reduce central sensitization inpersistent pain models (Haley et al. 1992; Hao and Xu 1996; Mao et al.1997). Chronic tension-type headache responds poorly to analgesics andnew treatments are badly needed (Rasmussen et al. 1991). The aim of thepresent study was to evaluate whether intravenous infusion of the NOSinhibitor, L-N⁰ methyl arginine hydrochloride (L-NMMA), is effective inthe treatment of this disorder.

[0424] Materials and Methods

[0425] Subjects

[0426] Sixteen patients with a diagnosis of chronic tension-typeheadache according to the criteria of the International Headache Society(Headache Classification Committee 1988) were recruited from theout-patient headache clinic at Glostrup Hospital. There were 12 womenand 4 men with a mean age (range) of 38.5 (23-52) years. Five patientswith coexisting infrequent migraine (£ one day/month) were accepted. Allpatients completed a diagnostic headache diary during a 4-week run-inperiod (Russell et al. 1992). At screening, a full physical andneurological examination, including 12-lead ECG were carried out. Bloodsamples for routine haematological and biochemical testing, and urinesample for urine analysis were taken. The patients were not allowed totake analgesics 12 hours prior to the treatment. Exclusion criteriawere: daily medication (including prophylactic headache therapy but notoral contraceptives); pregnant or breast feeding women; abuse ofanalgesics (corresponding to >2 gm of aspirin/day) or alcohol; serioussomatic or psychiatric diseases including depression (HamiltonDepression Score ³17 (Hamilton 1960)); ischemic heart disease; a supinediastolic blood pressure >90 mmHg or heart rate <50 beats per minute atstudy entry. All patients gave written informed consent to participatein the study, which was approved by the local ethics committee andconducted in accordance with the Declaration of Helsinki.

[0427] Procedures

[0428] Using a double-blind crossover design, the patients wererandomized to receive 6 mg/kg L-NMMA (Clinalfa, Switzerland) or placebo(isotone glucose) on two days with a typical episode of tension-typeheadache separated by at least one week. Randomization (Med.Stat) anddrug preparation were performed by staff not involved in the study. Themedication was given over 15 minutes into an antecubital vein (BraunPerfusor). The following parameters were measured at baseline and 15,30, 60 and 120 minutes post administration: headache intensity on a100-mm Visual Analog Scale (VAS) (0—no headache and 100—worst imaginableheadache) and on a Verbal Rating Scale (VRS) from 0-10 (0—no headache;5—moderate headache; 10—worst imaginable headache). Blood pressure andpulse rate were measured 5 minutes prior to administration of treatmentand at 5, 10, 15, 20, 25, 30, 60, 90 and 120 minutes postadministration. Twelve-lead ECG was monitored continuously. Any adverseevents were recorded. Patients trial unrelieved headache at 120 minutespost treatment were allowed to take rescue medication. All patients wereasked to record details of the following on a diary card at 4, 8, 12,16, 20 and 24 hours post administration: headache intensity on VRS, anymedication taken and adverse events. Between 4-7 days after eachtreatment, the patients returned to the clinic, the diary cards werecollected and any adverse events were noted.

[0429] Data Analysis and Statistics

[0430] Primary endpoint was the reduction of pain intensity over time onactive treatment compared to placebo. The secondary endpoints werereduction of pain intensity at 30, 60, 90 and 120 minutes post dosing onVAS and VRS compared to pre-treatment pain score within each treatment.Comparison of pain intensity on VAS, blood pressure and pulse rate overtime between treatments were performed with ANOVA. Paired-Samples T Testwas used to compare pre-treatment pain score on VAS with pain score at30, 60, 90, 120 minutes post dosing within each treatment. The sum ofdifferences between the pre-treatment VRS score and the VRS score at 30,60, 90, 120 minutes post dosing was calculated in order to obtained asummary measure of pain score for each treatment (Matthews et al. 1990).These sums of differences for each treatment were compared by WilcoxonSigned Rank test Five percent was accepted as level of significance.

[0431] Results

[0432] Treatment Efficacy

[0433] L-NMMA reduced pain intensity (VAS) over time significantly morethan placebo (p=0.007). Relative percent changes in pain intensity frombaseline are shovel in FIG. 14. Pain score was significantly reducedafter 30, 60, 90 and 120 minutes post treatment with L-NMMA (Table XII).There was no significant reduction in pain intensity following treatmentwith placebo at any time points. The pain intensity on VRS wassignificantly lover after treatment with L-NMMA than after treatmentwith placebo (p=0.02).

[0434] Adverse Events and Rescue Medication

[0435] The mean arterial blood pressure (MAP) and pulse rate changedsignificantly over time during treatment with L-NMMA compared withplacebo p=0.0001 and p=0.0001). The maximum increase in MAP was 12±2%and occurred 15 minutes post dosing. The maximum decrease in pulse ratewas 16±2% and occurred 10 minutes post dosing. The increase in MAP anddecrease in pulse rate are consistent with known pharmacologicalproperties of L-NMMA. Patients were unaffected by these changes. Sevenpatients reported subjective symptoms in relation to the L-NMMA infusionThese were: tiredness (2), dryness of the mouth (3), drowsiness (1),exhaustion (1), nausea (1) and a feeling of tingling in arm (1). Fourpatients reported subjective symptoms in relation to placebo treatment.These were: a feeling of tingling in arm (2) and shoulder (2), drynessof the mouth (1), warm sensation in the body (1) and drowsiness (1). Nopatients withdrew from the study because of side effects, Three patientstreated with L-NMMA and 7 patients treated with placebo used simpleanalgesics as rescue medication.

[0436] Discussion

[0437] There is ample experimental evidence showing that persistentactivity in peripheral nociceptors may lead to sensitization of spinaldorsal horn neurons partly via activation of N-methyl-D-aspartate (NMDA)receptors (Coderre et al. 1993). Since many of the effects of the NOVAreceptor activation are mediated through production of NO, it seemsprobable that NO plays an important role in the hyperalgesia ill thespinal cord (Meller and Gebhart 1993). In support for this, animalmodels have shown that NOS inhibitors reduce spinal dorsal hornsensitization induced by continues painful input from the peripheryHaley et al. 1992; Hao and Xu 1996; Roche et al. 1996). However, theefficacy NOS inhibitors have not previously been examined in patients.

[0438] Recently, it has been demonstrated that spinal dorsal hornsensitization due to prolonged nociceptive input from pericranialmyofascial tissues probably plays an important role in thepathophysiology of chronic tension-type headache (Bendtsen et al. 1996a,1996b; Jensen et al. 1997). Thus, it is likely that the analgesic effectof L-NMMA in chronic tension-type headache is due to reduction ofcentral sensitization at the level of the spinal dorsal horn.

[0439] In conclusion, the present study provides the first evidence ofan effect of NOS inhibitors in human chronic pain, and indicates thatthe effect of NO is via reduction of central sensitization probably atthe level of the dorsal horn/trigeminal nucleus. TABLE XII Pain scoreson VAS before treatment and at 30, 60, 90 and 120 minutes post dosing.Mean values (SD) are given. 30 60 90 120 Baseline minutes minutesminutes minutes L-NMMA 49 ± 16 38 ± 18* 35 ± 18* 34 ± 21* 33 ± 21*Placebo 44 ± 14 41 ± 17^(NS) 40 ± 17^(NS) 42 ± 16^(NS) 40 ± 17^(NS)

EXAMPLE 5

[0440] Muscular Factores are of Importance in Tension-Type Headache

[0441] Introduction

[0442] A recent study from by the present inventors demonstrated for thefirst time that chronic tension-type headache has a physiological basisand is caused at least partly by qualitative changes in the centralprocessing of sensory information (Bendtsen et al. 1996b). It wassuggested that muscular disorders are of primary importance for thedevelopment of central sensitization. To test this hypothesis, thepresent study of the psychophysical tests suggested in the IHSclassification (Headache Classification 1988) as well as thermal painsensitivity was conducted. The primary aim was to compare the mechanicaland the thermal pain sensitivity in tension-type headache patients withand without disorders or pericranial muscles. The secondary aim was tostudy the clinical characteristics of these patients.

[0443] Patients and Methods

[0444] Patients

[0445] Fifty-eight patients with tension-type headache fulfilling theIHS-criteria (Headache Classification 1988) were included (Table XIII).Twenty-nine patients had frequent episodic tension-type headache (ETH)and 29 patients had chronic tension-type headache (CTH). The patientswere recruited from the out-patient headache clinic at Gentofte Hospitaland complete physical and neurological examinations were done beforeentry. According to the primary aim patients with restricted tendernessin the pericranial muscles were favoured, since the percentage ofpatients associated with muscular disorders is 80-90% in consecutivepopulations (Jensen et al., 1996, Langemark et al., 1988). Furtherinclusion criteria were duration of tension-type headache for at leastone year and age between 18 and 70 years. The exclusion criteria were:migraine more than 1 day per month, cluster headache, trigeminalneuralgia, other neurological, systemic or psychiatric disorders,ingestion of major medications including prophylactics for migraine orother headaches, any form of drug abuse or dependency as dailyergotamine or large amounts of plain analgesics.

[0446] Thirty healthy subjects (12 males and 18 females) with a mean ageof 42 years (range 23-67 years) and without tension-type headache (<14days tension-type headache/year) were used as controls. Informed consentwas obtained and the study was approved by the local ethical committee.The present study was a part of a multifaceted study of tension-typeheadache, of which other parts have been published previously (Jensen,1996, Jensen and Olesen, 1996).

[0447] Procedure

[0448] All patients had to fill in a diagnostic headache diary during a4 week run-in period to ensure that they fulfilled the inclusioncriteria. Patients were instructed to fulfil the diary at the end ofeach day with headache and to record the mean intensity on a 0-3 scale,where 0 was no pain and 3 was severe incapacitating pain that requiresbed rest Mussel et al. 1992). The approximate start and disappearance ofheadache and the total intake of analgesics or other medications shouldalso be recorded. A standard dose of analgesics was defined as a doseequivalent to 1000 mg of aspirin. All patients were examined when freeof headache and were not allowed to have taken any analgesics on the dayof examination.

[0449] Examination

[0450] The examination was performed in a standardized way, which hasbeen described previously (Jensen, 1996, Jensen and Olesen, 1996). Allrecordings were performed by the same observer, the technician,throughout the entire study and the observer was blinded for thefollowing subdivision of patients. Before recordings of pain thresholdseach individual was carefully instructed to apply the saneinterpretation of ‘painful’ throughout the study. Initial test sessionswere applied to all subjects in order to familiarize them with the testconditions.

[0451] Palpation

[0452] Pericranial tenderness was evaluated by palpation of 9 pairs ofpericranial muscles and tendon insertions by the technician in astandardized, randomized procedure (Langemark and Olesen, 1989, Jensenet al., 1993b, Bendtsen et al., 1995a). Tenderness vats scored in eachlocation according to an ordinal scale from 0 to 3, and scores from allsites were summated. The maximum possible score was thus 54 points. ThisTotal Tenderness Score system (TTS) (Langemark and Olesen, 1987) haspreviously proved to be reliable Bendtsen et al., 1995). We havepreviously demonstrated that the most ideal cut-off point for separatingtension-tape headache subjects from non-headache subjects with respectto muscle tenderness was the 75% quartile of TTS obtained from a generalpopulation, whereas pressure algometry and EMG provided no furtherinformation (Jensen et al., 1996). In the following, TTS is used as theonly criteria for further subdivision patients with TTS above 9 (equalto the 75% quartile of TTS from healthy controls) was classified ashaving an association with muscular disorder (MUS), whereas those withTTS value at 9 or below were classified as unassociated with such adisorder (non-MUS).

[0453] Pressure Pain Thresholds

[0454] The pressure pain thresholds were evaluated bilaterally on thedistal dorsal part of the second finger, and in two cranial locations,one with interposed temporal muscle (Temp) and one without interposedmuscle in the parietal region (Par). A standardized and previouslyevaluated method was applied using an electronic pressure algometer(Somedic AB, Sweden) with an 0.79 cm² circular stimulation probe(Petersen et al., 1992, Jensen et al., 1986, Brennum et al., 1989). Twopain qualities were recorded, the Pressure Pain Detection Threshold(PPDT) defined as the threshold, where the pressure sensation becamepainful, and the Pressure Pain Tolerance (PPTO) defined as the thresholdwhere the patient would no longer tolerate the pain (Petersen et al.,1992). By pressing a hand held button the subjects indicated that thethreshold was reached, and the pressure was released immediately. Ifpatients did not activate the button, the experiment was terminated whenreaching 800 kPa in the cranial region and 1500 kPa in the fingers. Eachthreshold was calculated as the median value of 3 determinationsperformed with intervals of 10-15 seconds, and mean values of left andright sided recordings are presented in the following.

[0455] Thermal Pain Thresholds

[0456] Thermal thresholds were evaluated with a computerized version ofthe Thermotest (Somedic AB, Sweden) (Fruhstorfer et al., 1976, Yanmitskyet al., 1995). The thermode consisted of series-coupled Peltier elementsand measured 25×50 mm. The thenar region of the hand and the anteriorpart of the temporal region were examined bilaterally. Three stimulationqualities were recorded; the Warm Detection limit (WD) defined as thelowest temperature detected as warm, the Heat Pain Detection (HPD)defined as the temperature where the heat sensation became painful, aidthe Heat Pain Tolerance (HPTO) defined as the highest temperaturetolerated (Jensen et al., 1996, Jensen and Olesen, 1996). A baselinetemperature of 32° C. and a 1.0° C./sec rate of temperature change wasused. Heat stimulation was terminated when reaching 52° C., if thepatients had not responded before. By pressing a hand-held button thesubjects indicated when the actual threshold was reached. This value wasrecorded automatically and the stimulator returned to baseline. Eachthreshold was calculated as the average of S determinations performedwith intervals of 10-15 seconds, and mean values of left and right sidedrecordings are presented in the following.

[0457] Electromyography

[0458] EMG signals from the temporal and trapezius muscles were recordedbilaterally by a 4-channels electromyograph (Counterpoint, Dantec,Copenhagen). A standardized, previously described method was applied(Jensen et al., 1993). Data were collected during rest in the supineposition and during maximal voluntary contractions (MVC) (Jensen et al.1996). The root mean square (RMS) voltage was measured. Power spectrumwas calculated for the frequency range 0 to 1 kHz and Mean Frequencies(Mean F) were extracted (Jensen et al., 1996).

[0459] Statistics

[0460] Clinical data are presented as mean values with range (Table XIIIand XIV) and the psychophysical data as mean values ±SE. Mann-Whitncy'sU test was used for testing unpaired observations in patients with andwithout association with muscular disorders. Analysis of variance wasused to control for the variations in sex distribution among the groups.Spearnan's test was used for calculation of coefficients of correlation.Five percent was accepted as level of significance.

[0461] Results

[0462] Two patients (a male with the episodic and a male with thechronic subform.) were excluded from the present study due to deficientdiaries. The remaining 56 patients, 28 with CTH and 28 with ETHcompleted the studs and detailed clinical data with respect to theirassociation with muscular disorder are presented in Table XIII and TableXIV. Fourteen patients with chronic tension-type headache had a historyof coexisting migraine with a mean value of 7.3 days with migraine peryear, not significantly different from the 15 ETH patients, who had ahistory of 7.7 days with migraine per year. Similarly, there was nosignificant difference between the prevalence of migraine in patientswith muscular disorders compared to those without such disorder. Nosignificant variations in the clinical characteristics between patientswith and without disorders of pericranial muscles could be detected(Table XIII, XIV)

[0463] Tenderness Recorded by Manual Palpation.

[0464] According to the prior definition of association with musculardisorders, CTH patients associated with muscular disorder (MUS) had, asexpected, significantly higher TTS at 18.5 compared to 6.2 in thosewithout such an association (non-MUS) (p<0.0001). Similarly, ETH patentswith MUS had significantly higher TTS at 15.3 compared to 4.3 in thosewithout such an association (p<0.0001).

[0465] Pressure Pain Thresholds

[0466] Pressure pain detection and tolerance thresholds weresignificantly lower in CH patients associated with MUS compared tonon-MUS patients in all the examined locations (PPDT p<0.001; PPTOp<−0.05) (Table XV) (FIG. 15).

[0467] In patients with ETH, there were no significant differences inthe pressure pain thresholds and tolerances between subjects with orwithout association with muscular disorders in any of the examinedlocations (Table XVI) (FIG. 16).

[0468] Thermal Pain Thresholds

[0469] There were no significant differences in heat detection, heatpain and heat pain tolerance thresholds from the hands and the temporalregions between CTH patients with and without a muscular disorder.Similarly, no significant variations in thermal thresholds could bedetected in ETH patients with and without a muscular disorder.

[0470] Relation between Tenderness and Pain Thresholds

[0471] In CTH patients, the Total Tenderness Score (TTS) was highlycorrelated to the mechanical pain thresholds at the temporal region(Temp: ITS vs PPDT:r=−0.61, p<0.001; TTS vs PPTO:r=−0.65, p<0.001), anda similar tendency was seen at the parietal region (TTS vs PPDT r=4.59,p=0.003; TTS vs PPTO r=−0.24, p=0.27) and at the extracephalic region(Hands: TTS vs PPDT r=−0.36, p=0.06, TTS vs PPTO, r=0.48, p=0.02). Nosuch relations could be detected in ETH patients in any of the examinedlocations. When TTS was correlated to thermal thresholds no significantrelations appeared either in the chronic or the episodic form.

[0472] EMG

[0473] When EMG levels were recorded from the temporal and the trapeziusmuscles under resting conditions and during maximal voluntarycontraction, CTH patients with association to muscular factors hadsignificantly higher RMS values in their trapezius muscles duringresting condition compared to non-MUS patients (p=0.02). No othersignificant differences between the 2 subgroups in neither CTH nor ETHpatients appeared.

[0474] Relation to Healthy Controls

[0475] Tenderness by Manual Palpation

[0476] The mean Total Tenderness Score (TTS) in the 30 healthy controlswas 4.7 (quartiles 0-9) and was significantly lower than 9.8 (quartiles4-15) in those 28 patients with ETH (p=0.002). In CTH patients TTS was14.1 (quartiles 4-15) and significantly higher than in ETH patients(p=0.03) and in healthy controls (p<0.0001).

[0477] Pressure Pain Thresholds

[0478] Compared to healthy controls, CTH patients with non-MUS hadsignificantly higher pressure pain thresholds and tolerance thresholdsin all the examined locations (p<0.01), whereas the mechanicaltolerances tended to be significant lower in CTH patients with MUS(Fingers PPTO, p=0.07; Temp PPTO p=0.05). No significant differencescould be detected in the parietal regions or in pressure pain detectionthresholds from the other locations. When pressure pain detection andtolerance thresholds from the 2 subgroups of ETH patients were comparedto those from healthy controls no significant differences appeared.

[0479] Thermal Pain Thresholds

[0480] When the thermal thresholds were compared to healthy controls,significantly higher values of all the tested qualities were noted incephalic locations in those 10 CTH patients without association withmuscular disorders, whereas only warm detection values were higher onthe hands of these patients (Temporal:WD p=0.02, WPDT p=0.04, WPTOp=0.028; Hands: WD p=0.02). No significant variations in thermalthresholds could otherwise be detected in relation to healthy controls.

[0481] EMG

[0482] Only CTH patients associated with muscular factors hadsignificantly higher RMS values in the temporal (p=0.008) and thetrapezius muscles during rest (p=0.004) than healthy controls. No otherdifferences between patients and controls were noted.

[0483] Discussion

[0484] Relation between Tenderness and Pain Thresholds

[0485] In the present study highly significant inverse correlationsbetween TTS, pressure pain detection and tolerance thresholds were foundin patients with CTH corresponding with our recent study (Bendtsen etal.: 1996). Others have reported relatively small and clinicallyinsignificant relations (Schoenen et al. 1991a, Jensen et al., 1996,Sandrini et al., 1994)) and the pressure pain thresholds provided onlylimited diagnostic value (Jensen et al., 1996). This discrepancy may bedue to the fact that the pressure pain threshold represents the lowerend, and the pressure pain tolerance the upper end of a pain stimulusresponse curve. Tenderness obtained by manual palpation elicit painintensities between these extremes where the difference between patientsand controls is largest as discussed recently by Bendtsen et al(Bendtsen et al., 1996b, Bendtsen et al, 1996c). The diagnostic testsgiven in the IHS classification were previously assessed in a study froma highly specialized headache clinic (Snadrini et al., 1994) and insubjects from a general population (Jensen et al., 1996). In the latterstudy, 87% of subjects with chronic, and 66% of subjects with episodictension-type headache had a disorder of the pericranial muscles (Jensenet al., 1996). In the former, Sandrini et al reported that 61% ofpatients with episodic, and 66% of patients with chronic tension-typeheadache had disorder of pericranial muscles. An earlier study, whereonly EMG and pressure algometry were assessed, 72% were found to beassociated with disorders of pericranial muscles (Schoenen et al.,1991). Tenderness determined by manual palpation was previously found tobe the most sensitive and specific test for disorder of pericranialmuscles (Jensen et al., 1996) and was therefore applied as the only testto separate the 2 subforms in the present study.

[0486] Pathophysiological Mechanisms of the Disorderly of PericranialMuscles

[0487] It has been uncertain whether the increased, pericranialmyofascial tenderness was the cause or the effect of the pain. A recent,experimental study indicated, however, that tenderness precedes theinduced headache by several hours when tension-type headache is inducedby tooth clenching (Jensen et al., 1996). Possible mechanisms for thetenderness include 1) sensitization of peripheral myofascialnociceptors; 2) sensitization of second order neurons at thespinal/trigeminal level; 3) impaired central modulation of thenociceptive activity. As tension-type headache is a disease in man andnot known in animals, experimental animal models are of limited valuefor evaluation of these mechanisms. Fortunately, quantitative analysesof mechanical and thermal pain thresholds in humans can be used for thispurpose. Thermal pain- and tolerance thresholds are normal in most ofthese patients, which indicates that pain mediated by C-fibers isregistered and modulated normally. The present finding of markedlyincreased tenderness, slightly decreased mechanical but normal thermalthresholds at cephalic and extracephalic locations in CTH patientsassociated with muscular disorder, strongly indicates a hyperalgesicresponse to mechanical stimulation in these patients in line withprevious studies (Bendtsen et al., 1196c, Schoenen et al., 1991b,Langemark et al., 1989). This is also supported by our findings of ahighly significant inverse relation between tenderness and mechanicalthreshold. It has recently been demonstrated that due to centralsensitization, pain in CTH and in fibromyalgia may be mediated vialow-threshold mechanosensitive afferents projecting to dorsal hornneurons (Bendtsen et al., 1996c, Bendtsen et al. in press). This issupported by prior observations by Bendtsen et al., where an abnormalqualitative stimulus response function was found only in those 20 CTHpatients with the most pronounced tenderness whereas 20 patients withoutabnormal tenderness exhibited a fairly normal stimulus response curve(Bendtsen et al., 1996c). A further support for myofascial involvementis the finding of increased EMG amplitude levels only from thepericranial muscles of CTH patients associated with muscular disorders,whereas EMG levels otherwise were similar to those in controls. Themechanisms of pain in tension-type headache without association with amuscular disorder cannot be explained by simple allodynia and/orhyperalgesia as both mechanical and thermal pain thresholds from thesepatients were significantly increased compared to healthy controls,indicating a higher pain tolerability. Therefore, other mechanisms,probably in the central modulation of pain, must be considered. As theclinical features examined in the present study were fairly similarbetween the 2 subgroups in both the episodic and the chronic form it isvery likely, however, that several pathophysiological mechanisms areshared and further documentation about the fairly rare patients withtension-type headache without association with muscular disorders arehighly needed. Taken together our data strongly suggest that centralsensitization is of key importance in chronic tension-type headache withdisorders of pericranial muscles, whereas other mechanisms must beconsidered in patients without such disorders.

[0488] Relationship between Episodic and Chronic Tension-Type Headache

[0489] The present study is the first study which have examined thiswide variety of clinical characteristics and psychophysical tests inboth episodic and chronic tension-type headache. A marked difference innociceptive mechanical thresholds between the 2 subgroups in thechronic, but not in the episodic form was demonstrated, whereastenderness recorded by manual palpation was highly increased in both theepisodic and the chronic tension-type headache. A hypothesis of thepathophysiological evolution of tension-type headache can therefore becreated. In ETH patients with disorder of pericranial muscles, the mostlikely mechanism is a slightly increased input from myofascialnociceptors projecting to a widely normal central paw perception system.As chronic tension-type usually evolves from the episodic form(Langemark et al., 1989) it is suggested that prolonged painful inputfrom the periphery may sensitize the central nervous system and that thepain in CTH associated with muscular disorder thus may be due to acentral misinterpretation of the incoming signals at the dorsal horn ortrigeminal level. Such mechanisms have been demonstrated in animalmodels (Coderre et al., 1993, Mense et al., 1993, Hu et al., 1992,Hoheisel et al.: 1994), and irritative stimuli from myofascial, deeptissues are found to be much more effective for induction of centralsensitization than cutaneous stimuli (Yu et al., 1993). Musculardisorders may therefore be of major importance for the conversion ofepisodic into chronic tension-type headache. As the most frequentlyreported precipitating factors leading to tension-type headache arestress, mental tension and tiredness (Rasmussen et al., 1993, Clark etal., 1995, Ulrich et al., 1996), central supraspinal involvement isundoubtedly also involved, although precipitating factors may bedifferent from causative factors. Whether the precipitating factors andthe evolution of pain vary between the patients with and with disordersof pericranial muscles remains to be elucidated.

[0490] In conclusion, the present data indicate that the fine balancebetween periphery nociceptive input and their central modulation sternsto be disturbed in the majority of patients with tension-tape headache,namely those associated with muscular disorders. An a centralmisinterpretation of the incoming peripheral stimuli may be the result,a vicious circle is started and is probably maintained long time afterthe primary eliciting stimuli/stressor had stopped. Disorders ofpericranial muscles may therefore be of major importance for theconversion of episodic into chronic tension-type headache, whereas othermechanisms should be considered for those patients without suchdisorders. The present study supplements the understanding of theinteraction between peripheral and central changes in tension-typeheadache, and thereby, hopefully, will lead to a better understanding,prevention and treatment of the most prevalent tape of headache. TABLEXIII Clinical characteristics of patients with chronic tension-typeheadache (N = 28) Patients Patients with MUS without MUS Number (n) 1810 Males/females 7/11 7/3 Age (years) 48.1 (34-64) 49.4 (37-59)Years-with TH 24.8 (1-45) 26.2 (2-50) Frequency of TH 22.6 (15-28) 23.7(15-28) (days/28 days) Intensity  1.7 (1-2.5)  1.4 (1-2) (0-3 scale)Duration 11.3 (4.2-24)  9.5 (2.9-24) (hours) Medication  1.6 (0-3.1) 1.8 (0-4.1) (doses/day)

[0491] TABLE XIV Clinical characteristics of patients with episodictension-type headache(N = 28) Patients Patients with MUS without MUSNumber (n) 14 14 Males/females 1/13 5/9 Age (years) 39.8 (20-56) 42.6(21-59) Years with TH 20.2 (2-40) 19.6 (8-30) Frequency  9.6 (5-14) 10.0(6-14) (days/28 days) Intensity  1.7 (1.0-2.1)  1.8 (1.4-2.2) (0-3scale) Duration  9.7 (4.7-18)  8.6 (3.3-24) (hours) Medication  1.0(0-2)  0.8 (0-1.4) (doses/day)

[0492] TABLE XV Pressure pain detection and tolerance thresholds inpatients with chronic tension-type headache (N = 28). Mean values aregiven in kPa with SE in brackets. Patients Patients with MUS without MUS(n = 18) (n = 10) p-value Pain detection thresholds Fingers 262 (17) 374(23) p < 0.001 Temporal region 143 (9) 241 (18) p < 0.0001 Parietalregion 217 (18) 368 (28) p < 0.001 Pain tolerance thresholds Fingers 535(32) 776 (50) p < 0.001 Temporal region 252 (17) 394 (23) p < 0.0001Parietal region 471 (38) 521 (27) p = 0.04

[0493] TABLE XVI Pressure pain detection and tolerance thresholds inpatients with episodic tension-type headache (N = 28). Mean values aregiven in kPa with SE in brackets. Patients Patients with MUS without MUS(n = 14) (n = 14) p-value Pain detection thresholds Fingers 247 (12) 269(18) p = 0.14 Temporal region 162 (10) 169 (10) p = 0.72 Parietal region223 (16) 221 (16) p = 0.89 Pain tolerance thresholds Fingers 610 (34)595 (50) p = 0.47 Temporal region 317 (18) 327 (23) p = 0.98 Parietalregion 453 (23) 449 (30) p = 0.85

EXAMPLE 6

[0494] Gabapentin has a Prophylactic Effect in Chronic Tension-TypeHeadache

[0495] Introduction

[0496] GABA is an important inhibitory transmitter in the centralnervous system and it has been suggested that the encoding oflow-threshold mechanical threshold stimuli depends upon the presence ofa tonic activation of intrinsic glycine and/or GABAergic neurons (Yakshand Malmberg 1994). Gabapentin was synthesized to be a systemicallyactive GABA analogue and was found to have anticonvulsant effect.Although initially employed in humans to control seizures, recentclinical cases indicated that the agent showed efficacy in treatinghuman neuropathic pain states (Rosner et al 1996), and a considerablyeffect in several experimental pain models (Hwang and Yaksh 1996, Xiaoand Bennett 1996). The exact mechanism is not fully understood, butseveral mechanisms have been suggested. Binding studies fail to showaffinity for either GABA A or GABA B, although Gabapentin can increasethe rate of GABA synthesis and release. Furthermore, Gabapentin showedbinding affinity to the alpha-2-subunit of a calcium channel (Gee et al.1996), and these calcium channels are recently reported to play a veryexciting role in the genetic studies of migraine disorders. As the sideeffect profile of Gabapentin is favorable, the prophylactic effect ofGabapentin in a small open labeled pilot stud in patients with chronictension-tape headache was evaluated

[0497] Materials and Methods

[0498] Three patients with a diagnosis of chronic tension-type headacheaccording to the International Headache Society (Headache ClassificationCommittee 1958) were recruited from the outpatient headache clinic atGlostrup Hospital. The patients were males with a mean age of 42 years(range 35-49). The mean life time duration of chronic tension-typeheadache was 16 years (range 7-21). Two patients had a coexisting butinfrequent migraine. Exclusion criteria were: daily major medication(including prophylactic headache therapy); abuse of analgesics oralcohol; serious somatic or psychiatric diseases including depression.

[0499] Procedures

[0500] Using an open libeled design, patients fulfilled a diagnosticheadache diary during at least 4 weeks run-in period to ensure thediagnostic criteria Thereafter, the patients received Gabapentin(Neurontin®) tablets, initially 300 mg (one tablet) per day on day one,increasing with 300 mg (1 tablet) per day to 900 mg (3 tablets) on day3. The treatment period lasted 4 weeks, and during this period patientswere asked to continue with headache diaries, and record headacheintensity, frequency, duration, any medication taken and any possibleadverse events. At a follow up visit at day 29-32, diaries werecollected and any adverse events and evaluation of the treatment wererecorded. Due to the low number of patients, no statistical analysiswere done. The primary efficacy parameters were headache intensity,frequency and duration, and the mean values from the run-in period werecompared to those obtained during the treatment period.

[0501] Results

[0502] All patients completed the study. Headache intensity decreased35%, namely from 5.5 on a 0-10 VAS intensity scale during run-in periodto 3.6 during active treatment. Duration of the individual headacheepisode was reduced by 8%, and frequent, of headache decreased by 45%,namely from 23.5 days per 4 weeks during run-in period to 13 days per 4weeks during the active treatment period. The mean daily intake ofanalgesics decreased by 72% from 1.1 dose per day to 0.3 dose per day.One patient had excellent effect of Gabapentin with complete relief ofthe headache after 2 days treatment, another patient had a moderateeffect on headache intensity and frequency, and the third patient had nosignificant effect on any of efficacy parameters. Those two subjectswith good or excellent effect reported no side effects, whereas thethird patient who had no beneficial effect of Gabapentin complained ofsedation, vertigo and slight nausea. These side effects disappearedcompletely after cessation of the drug intake.

[0503] Discussion and Conclusion

[0504] The present results suggest a positive prophylactic effect ofGabapentin in chronic tension-type headache, which is in accordance withthe predictions made from the model involving central sensitizationprovided by the present invention. Although the exact mechanism ofaction of gabapentin is not fully elucidated, the preliminaryexperimental evidence are highly in favor of a pathophysiologicalexplanation of chronic tension-type headache, as caused by centralsensitization.

EXAMPLE 7

[0505] Dextromethorphan has a Prophylactic Effect in ChronicTension-Type Headache

[0506] Introduction

[0507] The common role played by NMDA antagonism in preclinical modelsis consistent with the observation that systemic ketamine reduces theallodynia, hyperalgesia and after sensation present in patients withperipheral pain injury, and the magnitude of the relief is, in general,proportional to dose. Dextromethorphan has been shown to reduce theafter sensation induced by repetitive stimuli in human volunteers (Priceet all 1994). Furthermore, the NMDA receptors are shown to act on theneuronal excitability via opening or closing of ion channels. Theincrease in intracellular calcium by such opening of the ion channels isbelieved to initiate a cascade of biochemical events, including pain.Effective blockade of these events is possible by NMDA antagonists,which are also highly effective in various human pain conditions relatedto central sensitization (Persson et al 1995). The major problem in thistreatment strategy is, however, the central side effects of most NMDAantagonists. Dextromethorphan has been known for decades as a coughsuppressant and has a very favorable side effect profile. Therefore theprophylactic effect of Dextromethorphan was evaluated in a small, openlabeled pilot study in patients with chronic tension-type headache.

[0508] Materials and Methods

[0509] Five patients with a diagnosis of chronic tension-type headacheaccording to the International Headache Society (Headache ClassificationCommittee 1988) were recruited from the outpatient headache clinic atGlostrup Hospital. There were 2 males and 3 females, and the mean agewas 45.4 yeas (range 39-48). The mean life time duration of chronictension-type headache was 12.2 years (range 4-25). One patient hadcoexisting but infrequent migraine. Exclusion criteria were: daily majormedication (including prophylactic headache therapy); abuse ofanalgesics or alcohol; serious somatic or psychiatric diseases includingdepression

[0510] Procedures

[0511] Using an open labeled design, patients fulfilled a diagnosticheadache diary during at least 4 weeks run-in period to ensure thediagnostic criteria. Thereafter, the patients received Dextromethorphan(Dexofan®) tablets at 30 mg each, three times per day. The treatmentperiod lasted 4 weeks, and during this period patients were asked tocontinue with headache diaries, and record headache intensity,frequency, duration, any medication taken and any possible adverseevents. At a follow up visit at day 29-32, diaries were collected andpossible adverse events and evaluation of the treatment were recorded.Due to the restricted number of patients, no statistical analysis weredone. The efficacy parameters were headache intensity, frequency andduration, and intake of simple analgesics. Mean values from the run-inperiod were compared to those obtained during the treatment period.

[0512] Results

[0513] All patients completed the study. The intensity of headache wasreduced 18% namely from 4.4 on a 0-10 VAS intensity scale during therun-in period to 3.6 during active treatment. Duration of the individualheadache episode was reduced by 11%, and frequency of headache decreasedby 4%, namely from 28 days per 4 weeks period during run-in to 27 daysper 4 weeks period during active treatment. Intake of analgesicsdecreased by 72% from a mean intake at 1.8 dose per day during run-inperiod to 0.5 dose per day during active treatment. Two patientsreported a marked effect with considerable relief of headache intensityand duration within very few days of treatment, one patient had a slightrelief of headache intensity and two patients reported no effect at all.Four patients reported no side effects, and marked side effects withsedation was reported in one patient, the patient with best clinicalresponse. These side effects diminished considerably after a dosereduction to 40 mg per day.

[0514] Discussion and Conclusion

[0515] The present results suggest a positive prophylactic effect ofDextromethorphan in chronic tension-type headache. The lack of effect insome patients may be due to a relatively small dosage. Although theexact mechanism of Dextromethorphane is not fully elucidated, thepreliminary evidence in experimental pain model is in favor of an effectaccording to the present, pathophysiological model of chronictension-type headache, i.e. the central sensitization model of thepresent invention,

EXAMPLE 8

[0516] Possible Mechanisms of Action of Action of Nitric Oxide SynthaseInhibitors in Chronic Myofascial Pain

[0517] Pain from the musculoskeletal system is probably the most commontype of chronic pain (Magni et al. 1990). Progress in basic painresearch has increased our knowledge about the mechanisms underlyingchronic myofascial pain (sense 1993). Thus, substantial experimentalevidence indicates that central sensitization generated by prolongednociceptive input from the periphery plays an important role in thepathophysiology of chronic pain particularly from myofascial tissues(Woolf 1983, Hu et al. 1992; Woolf and Doubell 1994; Bendtsen et al.1996a). The freely diffusible gas nitric oxide (NO) is assumed to be ofimportance for the development of central sensitization (McMahon et al.1993; Meller and Gebhart 1993). Thus, nitric oxide synthase (NOS)inhibitor reduce central sensitization in animal models of persistentpain (Haley et al. 1992; Hao and Xu 1996; Mao et al. 1997). We recentlydemonstrated that NOS inhibition has an analgesic effect in patientswith chronic myofascial pain (Ashina et al. 1998a). However, themechanisms of this effect have so far been unknown. The aim of thepresent study was to investigate whether the NOS inhibitor, L-N^(G)methyl arginine hydrochloride (L-NMMA), modulates muscle hardness (Sakaiet al. 1995) and myofascial tenderness (Jensen et al. 1998) in patientswith chronic myofascial pain.

[0518] Materials and Methods

[0519] Subjects

[0520] Sixteen patients with a diagnosis of chronic tension-typeheadache according to the criteria of the International Headache Society(Headache Classification Committee 1988) were included (Table XVII).Five of the patients had coexisting infrequent migraine (<fourdays/year). The patients were recruited from the out-patient headacheclinic at Glostrup University Hospital without respect to presence orabsence of myofascial tenderness. All patients underwent a generalphysical and a neurological examination and completed a diagnosticheadache diary during a 4-week run-in period (Russell et al. 1992).Exclusion criteria were; daily medication (including prophylacticheadache therapy but not oral contraceptives); abuse of analgesics(corresponding to >2 gm of aspirin/day); serious somatic or psychiatricdiseases including depression (Hamilton Depression Score #17 (Hamilton1960)). Patients were examined and treated during a typical day oftension-type headache. All patients gave written consent to participatein the study, which was approved by the Danish Board of Health and thelocal ethics committee. The study was conducted in accordance with theDeclaration of Helsinki.

[0521] Apparatus

[0522] Muscle hardness. The muscle hardness of the trapezius muscle wasmeasured with a hardness meter, which has previously been described indetail (Horikawa et al. 1993). In brief, the hardness meter consists ofa laser distance sensor and a pressure terminal with a surface area of 1cm². The muscle hardness is estimated by recording the relation betweenthe applied pressure and the displacement of the skin over the muscle.All calculations are performed by a software-program in order to avoidobserver bias. Hardness is expressed in kPa/cm. We have previouslydemonstrated that the hardness meter can measure muscle hardnessreliably if the same observer is used throughout a study (Ashina et al.1998b).

[0523] Pressure pain thresholds. An electronic pressure algometer(Somedic AB, Stockholm, Sweden) was used to measure pressure painthresholds. The algometer has been described in detail elsewhere (Jensenet al. 1986). A circular stimulation probe (0.50 cm²) and a pressureloading rate of 22 kPa/s (1 kPa=10³ N/m²) were used.

[0524] Methods

[0525] The recordings were performed in a standardized manner by thesane observer, a trained technician (HA), throughout the study. Allparameters were recorded at baseline, 60 and 120 minutes after start ofinfusion. The trial was designed as a double blind, placebo controlled,crossover study. The first part of the study examined the analgesiceffect of L-NMMA and has previously been described in detail (Ashina etal. 1998a). Briefly, patients were randomized to receive 6 mg/kg L-NMMA(Clinalfa, Switzerland) or placebo (isotonic glucose) over 15 minutesinto an antecubital vein on two days separated by at least one week. Thepatients mere not allowed to take analgesics 12 hours prior to theexamination. Headache intensity as measured on a 100 mm Visual AnalogScale (VAS) (0—no headache and 100—worst imaginable headache) before,during and after start of infusion.

[0526] Muscle hardness. The muscle hardness was measured at a standardanatomical point on the trapezius muscle on the non-dominant side, aspreviously described (Ashina et al. 1998b). Briefly, the point waslocated on the center of the descending part of the trapezius musclemidway between the processus spinosus of the seventh cervical vertebraand the acromion. The muscle hardness was calculated as the mean of fiveconsecutive determinations. All recordings were stored in the computer,and they were not analyzed before the study was completed.

[0527] Total tenderness. Tenderness of percranial myofascial tissues wasrecorded according to the Total Tenderness Scoring system (Langemark andOlesen 1987), which has previously proved to be reliable (Bendtsen etal. 1995). Eight pairs of muscles and tendon insertions (masseter,temporal, frontal, sternocleidomastoid and trapezius muscles, coronoidand mastoid processes, and neck muscle insertions) were palpated.Tenderness was scored on a 4-point (0-3) scale at each location (localtenderness score) and values from left and right sides were summed to aTotal Tenderness Score (TTS) (maximum possible score=48).

[0528] Pressure pain thresholds. Pressure pain detection thresholds(PPDTs) were measured at the dorsum of the second finger (middlephalanx) and at a fixed point at the anterior part of the temporalmuscle as previously described (Bendtsen et al. 1996b). Measurementswere performed at the non-dominant side. The PPDT was defined as thepressure at which the sensation changed from pressure alone to pain. Thesubject indicated that the pain threshold was reached by pressing ahandheld button. The algometer display was thereby Afrozen@ and thepressure was immediately released. Each threshold was calculated as themean of five consecutive determinations performed with intervals ofapproximately 30 seconds.

[0529] Data Analysis and Statistics

[0530] Results are presented as means SDs. For each of the variables,the sum of the differences between the pre-treatment value and each ofthe post-treatment values was calculated in order to obtain a summarymeasure of effect for each treatment (Matthews et al. 1990). The summaryscores calculated for active treatment and placebo were compared by useof the Wilcoxon Signed Ranks test Within each treatment pretreatmentvalues were compared with values at 60 and 120 minutes post dosing byuse of the Wilcoxon Signed Ranks test Five percent was accepted as levelof significance.

[0531] Results

[0532] Muscle hardness. The summary scores of muscle hardness of thetrapezius muscle was reduced significantly more following treatment with1 compared with placebo (p=0.04) (FIG. 17). Compared to baseline,hardness was significantly reduced at 60 and 120 minutes after treatmentwith L-NMMA (p=0.04 and p<0.05, respectively). There alas no significantreduction in muscle hardness at any time after treatment with placebo(Table XVIII).

[0533] Tenderness. The summary of tenderness score tended to be reducedmore following treatment with L-NMMA than with placebo, but thedifference was not statistically significant (p=0.11) (FIG. 18).However, compared to baseline TTS was significantly reduced at 60 and120 minutes after treatment with L-NMMA compared with pretreatmentvalues (p=0.007 and p=0.008, respectively). There was no significantreduction in TTS at any time after treatment pith placebo (Table XVIII).

[0534] Pressure pain thresholds. There was no significant differencebetween PPDTs recorded during treatment with L-NMMA and placebo (finger:p=0.78 and temporal region: p=0.77). There were also no changes in PPDTsat 60 and 120 minutes after treatment with L-NMMA compared withpre-treatment values neither in the finger nor in the temporal region(Table XVIII). Compared to baseline PPDT decreased significantly in thefinger (p=0.04), but not in the temporal region following treatment withplacebo (Table XVIII).

[0535] Pain intensity. Pain intensity was significantly more reducedfollowing treatment with L-NMMA than following treatment with placebo(FIG. 19) as previously reported (Ashina et al. 1998a). Pain scores weresignificantly reduced at each time point after treatment with L-NMMA,while there was no significant reduction in pain intensity at any timepoint after treatment with placebo (FIG. 19).

[0536] Discussion

[0537] In the present study, chronic tension-type headache was used as amodel for chronic myofascial pain, since nociception from myofascialtissues probably plays an important role in the pathophysiology ofchronic tension-type headache. Thus, several studies have consistentlyreported increased myofascial tenderness as the most prominent abnormalfinding in patients with chronic tension-type headache (Langemark andOlesen 1987; Jensen et al. 1993; Jensen et al. 1998; Bendtsen et al.1996b; Lipchik et al. 1997; Ashina et al. 1998b). A further support formyofascial involvement is the recent findings of increased musclehardness (Sakai et al. 1995) and a positive correlation between musclehardness and tenderness in chronic tension-type headache (Ashina et al.1998b). The mechanisms contributing to the increased tenderness andmuscle hardness are unknown. Recently it has been suggested that theincreased tenderness in patients with chronic tension-type headache andfibromyalgia may be due to central sensitization of spinal dorsal hornneurons induced by prolonged nociceptive input from myofascial tissues(Bendtsen et al. 1996a, 1997; Jensen et al. 1998). An investigation ofmyofascial tenderness and muscle hardness in patients with chronictension-type headache may therefore contribute to our understanding ofmyofascial pain.

[0538] Animal experiments have suggested that NO is an importanttransmitter in pain pathways of the spinal cord and that sensitizationof these pathways may be caused by or associated with activation of NOSand the generation of NO (Haley, et al, 1992; Meller et al. 1992; Mellerand Gebhart 1993). In support for this, it has recently been shown inanimal models of persistent pain that NOS inhibitors reduce spinaldorsal horn sensitization induced by continues painful input from theperiphery (Meller et al. 1994; Roche et al. 1996; Mao et al. 1997). Inaddition, we have recently demonstrated that NOS inhibition has ananalgesic effect in patients with chronic myofascial pain (Ashina et al.1998a). In the latter study we found that headache intensity wassignificantly reduced during treatment with L-NMMA compared withplacebo. The present study provides important information about themechanisms of the antinociceptive action of NOS inhibition in chronicmyofascial pain. We found that both muscle hardness and tenderness weresignificantly reduced at each time point after treatment with L-NMMA,while there was no significant reduction in muscle hardness ortenderness at any time after treatment with placebo. Although thetenderness was significantly reduced, the reduction of tendernesscompared to placebo was not significant. This may be due to lack ofstatistical power. The muscle hardness was significantly reducedfollowing treatment with L-NMMA compared to placebo. Althoughstatistically significant, the reduction of hardness was very small.This is understandable because the increased hardness is a rather stablefeature (Ashina et al. 1998c) which is not easy to change in an acuteexperiment. Similar arguments apply to myofascial tenderness (Jensen etal. 1998). Long term treatment could perhaps result in larger changes.The importance of the present results lies in the proof of concept notin the magnitude of the effect. The pressure pain detection thresholdsin the finger and temporal region were largely unchanged followingtreatment with L-NMMA This indicates that L-NMMA did not significantlyalter general pain sensitivity. The questions are what mechanismsleading to the increased muscle hardness and tenderness; how L-NMMAmodulates muscle hardness and tenderness; and whether the effects ofL-NMMA observed in the present study are due to an action in muscle orin the CNS? It has been shown that the central neuroplastic changes mayincrease the drive to motor neurons both at the supraspinal and thesegmental level (Woolf 1983). In this way it is possible that sustainedmuscle contraction due to increased hypersensitivity in CNS contributesto increased muscle hardness and tenderness in chronic tension-typeheadache. This is supported by recent findings of increased tendernessand muscle activity in patients with chronic tension-type headache wasfound not only on days with headache but also on days without headache(Lipchik et al. 1997; Ashina et al. 1998b; Jensen et al. 1998).Furthermore, muscle hardness recorded in patients on days with headachedid not differ from hardness recorded on days without headache (Ashinaet al. submitted 1998b). Collectively, these results indicate thatpermanently altered muscle hardness, tenderness and muscle activity mayreflect an increased input from myofascial nociceptors with subsequentsensitization of second order neurons. L-NMMA inhibits all three typesof NOS (endothelial NOS, neuronal NOS and inducible NOS) (Southan andSzabo 1996) and rich sources of nNOS are present not only in nervoustissue but also in all striated muscles of mammals (Grozdanovic et al.1995). In addition to nNOS, skeletal muscles also contain eNOS. Recentstudy has demonstrated that NO has important physiological functions inskeletal muscles such as promoting relaxation and modulating increasesin contraction (Kobzik et al. 1994). Interestingly, contractile functionof muscles was enhanced by blockers of NO synthase Kobzik et al. 1994).Because of this inverse correlation between contractile function andnNOS activity, one could expect that L-NMMA will induce the contractionof muscle with subsequent increase of muscle hardness and tenderness.However, in the present study we observed the reduction of musclehardness and tenderness following treatment with L-NMMA. Thus, theeffects of L-NMMA observed in the present study may be due to reductionof sensitization of second order neurons receiving input from myofascialtissues and locating at the level of the spinal dorsal horn/trigeminalnucleus.

[0539] The increased muscle hardness and tenderness may reflect a tissueoedema or metabolic alterations due to microcirculatory disturbance(Henriksson et al. 1993). It is possible that L-NMMA acts directly inmyofascial tissues or nociceptors located in such tissues. Thus, theability of NOS inhibitors to cause vasoconstriction (Rees et al. 1990)may prevent inflammatory mediators and algogenic substances involved inhardness and tenderness from reaching their site of action (Haley et al.1992). In addition, it has been demonstrated that NOS inhibitors haveantinociceptive effect after peripheral administration (Haley et al.1992; Kindgren-Milles and Arndt 1996; Nakamura et al. 1996). However,the exact role of NO in the periphery is still far from understood, andadditional research is needed to clarify whether NO may activate orsensitize peripheral nociceptors. The antinociceptive effect of NOSinhibition might also result from non-specific effects elicited byL-NMMA, such as changes in blood pressure and pulse rate. Mean arterialblood pressure and pulse rate were continuously monitored in the presentstudy. We found that the peak increase in mean arterial blood pressure(12%) and maximum decrease in pulse rate (16%) occurred 15 and 10minutes respectively after treatment with L-NMMA. The difference in themean arterial blood pressure and pulse rate between L-NMMA and placebodisappeared 60 minutes after start of infusion (Ashina et al. 1998a). Incontrast, the antinociceptive effect on headache intensity and thereduction of muscle hardness and tenderness lasted at least 120 minutesafter start of infusion. It therefore seems unlikely that the observedeffects of L-NMMA were caused by hypertensive effects of the agent. Inconclusion, the present study indicates that the NOS inhibitor L-NMMAelicits its antinociceptive effect in myofascial pain by modulation ofnociceptive information from myofascial tissues. This antinociceptiveeffect is probably caused by reduction of central sensitization at thelevel of the spinal dorsal horn/trigeminal nucleus. TABLE XVII Clinicaldata on patients. Patients Number 16 Females/males 12/4 Age, years 39(23-52) Headache frequency, days/4 weeks 22 (15-28)

[0540] TABLE XVIII Muscle hardness, Total Tenderness Score (TTS) andpressure pain detection thresholds (PPDT) in the finger and the temporalregion (TR) recorded before and 60 and 120 minutes after start of theinfusion of L-NMMA or placebo. Baseline 60 minutes 120 minutes Musclehardness L-NMMA 107″ 17 101″ 17* 101″ 17* Placebo 106″ 18 104″ 17^(NS)105″ 22^(NS) TTS L-NMMA  18″ 11  15″ 11**  14″ 11** Placebo  17″ 12  16″13^(NS)  15″ 13^(NS) PPDT/finger L-NMMA 455″ 155 436″ 129^(NS) 449″144^(NS) Placebo 457″ 141 435″ 143^(NS) 420″ 130* PPDT/TR L-NMMA 279″108 264″ 86^(NS) 277″ 95^(NS) Placebo 274″ 104 271″ 109^(NS) 262″95^(NS)

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1. A method for treatment or prevention of tension-type headache in aperson in need of such treatment, comprising administering an amount ofan agent effective to interact with neuronal transmission connected withpain perception, so as to prevent or reduce central sensitization, withthe proviso that said interaction is not performed by administeringethyl 2-amino-6-(4-fluorobeznylamino)-3-pyridylcarbamate or anarylglycinamide derivative as defined herein.
 2. A method according toclaim 1 for treatment of tension-type headache in a person in need ofsuch treatment, comprising administering an amount of an agent effectiveto interact with neuronal transmission connected with pain perception,so as to prevent or reduce central sensitization.
 3. A method accordingto claim 1 for prevention of tension-tape headache in a person in needof such treatment, comprising administering an amount of an agenteffective to interact with neuronal transmission connected with painperception, so as to prevent or reduce central sensitization.
 4. Amethod according to claim 1, wherein the agent is an agent which iscapable of substantially normalizing a pathological qualitativelyaltered stimulus-response function.
 5. A method according to claim 1,wherein the agent is an agent which is capable of substantiallynormalizing a pathological abnormally low pain threshold.
 6. A methodaccording to claim 1, wherein the agent is an agent which is capable ofsubstantially reducing a pathological increased pericranial musclehardness.
 7. A method according to claim 1, wherein the agent is anagent which is capable of substantially reducing a pathologicalincreased pericranial myofascial tenderness.
 8. A method according toclaim 1, wherein the agent is an agent which is capable of substantiallypreventing or reducing pain, tenderness or hardness in pericranialmuscle induced by experimental tonic muscle contraction, or normalizinga qualitatively altered stimulus-response function induced byexperimental tonic muscle contraction, or normalizing a reduced painthreshold induced by experimental tonic muscle contraction.
 9. A methodaccording to claim 1, wherein the agent is an agent which is capable ofsubstantially preventing or reducing pain, tenderness or hardness inpericranial muscle induced by intra muscular infusion of algogenicsubstances, or preventing or normalizing a qualitatively alteredstimulus-response function induced by intra muscular infusion ofalgogenic substances or normalizing a reduced pain threshold induced byintra muscular infusion of algogenic substances.
 10. A method accordingto claim 1, wherein the agent is an agent which is capable ofsubstantially preventing or reducing pain, tenderness or hardness inpericranial muscle induced by stimulation of nociceptive afferents inmyofascial tissues or preventing or normalizing a qualitatively alteredstimulus-response function induced by stimulation of nociceptiveafferents in myofascial tissues or normalizing a reduced pain thresholdinduced by stimulation of nociceptive afferents in myofascial tissues.11. A method according to claim 1, wherein the agent is an agent whichis capable of substantially preventing or reducing secondary allodyniaor secondary hyperalgesia induced by stimulation of nociceptiveafferents in myofascial tissues.
 12. A method according to claim 1,wherein the agent is an agent which is capable of substantiallypreventing or reducing wind-up induced by repetitive stimulation ofnociceptive afferents in the pericranial region.
 13. A method accordingto claim 1, wherein the agent is an agent which is capable ofsubstantially preventing or reducing secondary allodynia or secondaryhyperalgesia induced by nociceptive input in an experimental animalmodel.
 14. A method according to claim 1, wherein the agent is an agentwhich is capable of substantially preventing or reducing wind-up inducedby repetitive stimulation of nociceptive afferents in an experimentalanimal model.
 15. A method according to claim 1, wherein the agent is anagent which is capable of substantially preventing or reducing increasedreceptive field size of second order neurons induced by nociceptiveinput in an experimental animal model.
 16. A method according to claim1, wherein the agent is an agent which is capable of substantiallypreventing or reducing an increased excitability of the flexion reflexinduced by nociceptive input in an experimental animal model.
 17. Amethod according to claim 1, wherein the agent is an agent which iscapable of substantially preventing or reducing central sensitizationinduced by nociceptive input in an experimental animal model.
 18. Amethod according to claim 1 for treatment or prevention of tension-typeheadache in a person in need of such treatment, the patient having aqualitatively altered stimulus/response function in connection withnociception, comprising administering an amount of an agent effective tointeract with neuronal transmission connected with pain perception, soas to obtain a substantial normalization of an otherwise qualitativelyaltered stimulus/response function in connection with nociception.
 19. Amethod according to claim 1, wherein the treatment or prevention oftension-type headache is not accompanied by a substantial reduction ofmuscle tension.
 20. A method according to claim 1, wherein theinteraction comprises interaction with neuronal transmission connectedwith second order nociceptive neurons.
 21. A method according to claim1, wherein the interaction comprises a reduction of input to secondorder nociceptive neurons.
 22. A method for treating tension-typeheadache in a person which comprises administering an agent in an amounteffective to alleviate said headache, said agent being an agent capableof altering the relationship of pain intensity to pressure intensitywhen the trapezoid muscle is palpated at different pressure intensitiesin said person.
 23. A method according to claim 22 wherein therelationship is substantially linear in the untreated persons, andsubstantially non-linear in the treated persons.
 24. A method accordingto claim 23, wherein the relationship is positively accelerating in thetreated person.
 25. A method according to claim 24, wherein the rate ofacceleration of pain intensity with pressure intensity is substantiallyconstant.
 26. A method according to claim 25, wherein the relationshipin the treated persons is substantially the same as in control personswho did not have tension-type headache and who were treated with aplacebo.
 27. A method according to claim 1, wherein the interaction isone which in a panel of test persons suffering from increased myofascialtenderness with disorder of pericranial muscle in connection withtension-type headache still transform a substantially linear painintensity perception in response to pressure intensity in trapeziusmuscle into a curve (C) of which the values of pain intensity are lowerthan the linear pain intensity perception and wherein the curve (C) canbe described substantially as a power function and is a curve which issubstantially linear in a double logarithmic plot and whereinsubstantially each of the values of curve (C) is at the most 20% higherthan the value of the corresponding curve produced for a test panel ofhealthy controls.
 28. A method according to claim 27, whereinsubstantially each of the values of curve (C) is at the most 10% higherthan the value of the corresponding curve produced for a test panel ofhealthy controls.
 29. A method according to claim 1, wherein theinteraction is effected by administering an effective amount of an agentinteracting with neuronal transmission connected with pain perception,the administration being performed substantially at least once daily andbeing continued for a period of at least one month.
 30. A methodaccording to claim 29, wherein the administration is being continued fora period of at least one month and less than 10 years.
 31. A methodaccording to claim 29, wherein the administration is being continued fora period of at least one month and less than 5 years.
 32. A methodaccording to claim 29, wherein the administration is being continued fora period of at least one month and less than 2 years.
 33. A methodaccording to claim 29, wherein the administration is being continued fora period of at least one month and less than 1 year.
 34. A method fortreatment or prevention of tension-type headache in a person in need ofsuch treatment comprising administering an amount of an agent which, inthe peripheral and/or central nervous system, is effective tospecifically interact with neuronal transmission connected with painperception by a) substantially antagonizing the action of glutamate,5-HT, GABA, nitric oxide, nitric oxide synthase, guanylate cyclase,cyclic guanylate monophosphate (cGMP), CGRP, substance P, neurokinin A,neurokinin B, bradykinin, PACAB, adenosine, glycine, his tin,neurotrophins, Na⁺ ions or Ca²⁺ ion channels, or by b) substantiallypotentiating the action of adenosine, galanine or norepinephrine, withthe proviso that said agent is not ethyl2-amino-6-(4-fluorobenzylamino)-3-pyridylcarbamate.
 35. A methodaccording to claim 34, wherein the agent is an agent capable ofinteracting with neuronal transmission connected with pain perception,so as to prevent or reduce central sensitization.
 36. A method accordingto claim 34, wherein the agent is an agent capable of interacting withneuronal transmission connected with pain perception, so as to obtain asubstantial normalization of a qualitatively altered stimulus/responsefunction in connection with nociception.
 37. A method according to claim1, wherein the agent is an agent which, in the peripheral and/or centralnervous system, is capable of substantially inhibiting the production ofglutamate or substantially inhibiting the release of glutamate orsubstantially counteracting the action of glutamate or substantiallyinhibiting the binding of glutamate to receptors for glutamate.
 38. Amethod according to claim 34, wherein the agent comprises a glutamatereceptor antagonist.
 39. A method according to claim 37, wherein theagent comprises a glutamate receptor antagonist.
 40. A method accordingto claim 39, wherein the agent comprises an NMDA glutamate receptorantagonist.
 41. A method according to claim 40, wherein the agentcomprises a competitive NMDA glutamate receptor antagonist.
 42. A methodaccording to claim 41, wherein the agent comprises a nitrogen-containingheterocyclic compound selected from the group consisting of diacidicpiperidines, diacidic piperazines and phosphono amino acids orderivatives of any of the above which are competitive NMDA antagonistsor prodrugs thereof.
 43. A method according to claim 40, wherein theagent comprises a non-competitive NMDA glutamate receptor antagonist.44. A method according to claim 43, wherein the agent is selected from agroup consisting of polycyclic amines, tricyclic antidepressants,adamantanamines, arylcyclohexylamines, arylcyclohexylamines, opioidderivatives, glycylamides, piperidinylethanols, piperidinylethanols,diguanidines, g-aminobutyric acid derivatives, polycyclic amines orderivatives of any of the above which are non-competitive NMDAantagonists or prodrugs thereof.
 45. A method according to claim 40,wherein the agent comprises a tricyclic antidepressant or derivativesthereof which are NMDA glutamate receptor antagonists or prodrugsthereof.
 46. A method according to claim 40, wherein the agent is aselected from the group consisting of γ-aminobutyric acid derivatives,polycyclic amines or derivatives of any of the above which are NMDAglutamate receptor antagonists or prodrugs thereof.
 47. A methodaccording to claim 39, wherein the agent comprises a non-NMDA glutamatereceptor antagonist.
 48. A method according to claim 47, wherein theagent comprises a competitive non-NMDA glutamate receptor antagonist.49. A method according to claim 47, wherein the agent comprises anon-competitive non-NMDA glutamate receptor antagonist.
 50. A methodaccording to claim 47, wherein the agent comprises an AMPA glutamatereceptor antagonist.
 51. A method according to claim 47, wherein theagent is a competitive AMPA glutamate receptor antagonist.
 52. A methodaccording to claim 51, wherein the agent is selected from the groupconsisting of quinoxalinediones, dihydraquinolones, diacidicdecahydroisoquinolines, amino acid isoxazoles, indoleoximes orderivatives of any of the above which are competitive AMPA receptorantagonists or prodrugs thereof.
 53. A method according to claim 47,wherein the agent comprises a non-competitive AMPA glutamate receptorantagonist.
 54. A method according to claim 53, wherein the agent isselected from the group consisting of 2,3-benzodiazepines, phthalazinesor derivatives of any of the above which are non-competitive AMPAreceptor antagonists or prodrugs thereof.
 55. A method according toclaim 47, wherein the agent comprises a kainic acid receptor antagonist.56. A method according to claim 55, wherein the agent comprises acompetitive kainic acid receptor antagonist.
 57. A method according toclaim 56, wherein the agent comprises an indoleoxime or derivativesthereof which are competitive kainic acid receptor antagonists orprodrugs thereof.
 58. A method according to claim 55, wherein the agentcomprises a non-competitive kainic acid receptor antagonist.
 59. Amethod according to claim 47, wherein the agent comprises a metabotropicglutamate receptor antagonist.
 60. A method according to claim 59,wherein the agent comprises a competitive metabotropic glutamatereceptor antagonist.
 61. A method according to claim 59, wherein theagent comprises a non-competitive metabotropic glutamate receptorantagonist.
 62. A method according to claim 37, wherein the agentcomprises a metabotropic glutamate receptor agonist.
 63. A methodaccording to claim 62, wherein the agent is selected from the groupconsisting of phenylglycines, amino acid indanes, phosphono amino acidsor derivatives of any of the above which are metabotropic glutamatereceptor agonists or prodrugs thereof.
 64. A method according to claim1, wherein the agent is an agent which, in the peripheral and/or centralnervous system, is capable of substantially inhibiting the production of5-HT or substantially inhibiting the release of 5-HT or substantiallycounteracting the action of 5-HT or substantially inhibiting binding of5-HT to 5H_(2,3) receptors.
 65. A method according to claim 34, whereinthe agent comprises a 5-HT_(2,3) receptor antagonist.
 66. A methodaccording to claim 64, wherein the agent comprises a 5-HT_(2,3) receptorantagonist.
 67. A method according to claim 66, wherein the agent isselected from the group consisting of tropan derivatives, polycyclicamines or derivatives of any of the above which are 5-HT_(2,3) receptorantagonists or prodrugs thereof.
 68. A method according to claim 1,wherein the agent is an agent which, in the peripheral and/or centralnervous system, is capable of substantially enhancing the production ofGABA or substantially enhancing the release of GABA or substantiallyenhancing the action of GABA or substantially activating receptors forGABA.
 69. A method according to claim 68, wherein the agent comprises aGABA activity enhancer.
 70. A method according to claim 69, wherein theagent comprises a benzodiazepine or a derivative thereof which is a GABAactivity enhancer or prodrugs thereof.
 71. A method according to claim34, wherein the agent comprises a GABA uptake inhibitor.
 72. A methodaccording to claim 70, wherein the agent comprises a GABA uptakeinhibitor.
 73. A method according to claim 72, wherein the agent isselected from the group consisting of carboxypiperidine derivatives,carboxypyridine derivatives, 3-hydroxyisoxazoles, nipecotic acidderivatives, guvacine derivatives or derivatives of any if the abovewhich are GABA uptake inhibitors or prodrugs thereof.
 74. A methodaccording to claim 68, wherein the agent comprises a GABA-A agonist. 75.A method according to claim 74, wherein the agent is selected form thegroup consisting of γ-aminobutyric acid derivatives, 3-hydroxyisoxazolesor derivatives of any of the above which are GABA-A agonists or prodrugsthereof.
 76. A method according to claim 68, wherein the agent comprisesa GABA transaminase inhibitor.
 77. A method according to claim 76,wherein the agent comprises a g-aminobutyric acid derivative orderivatives thereof which are GABA transaminase inhibitors or prodrugsthereof.
 78. A method according to claim 1, wherein the agent is anagent which, in the peripheral and/or central nervous system is capableof substantially inhibiting the production of nitric oxide orsubstantially counteracting the action of nitric oxide or substantiallyinhibiting the production of nitric oxide synthase (NOS) orsubstantially counteracting the action of nitric oxide synthase (NOS).79. A method according to claim 34, wherein the agent comprises a nitricoxide inhibitor.
 80. A method according to claim 78, wherein the agentcomprises a nitric oxide inhibitor.
 81. A method according to claim 34,wherein the agent comprises an NOS inhibitor.
 82. A method according toclaim 8D, wherein the agent comprises an NOS inhibitor.
 83. A methodaccording to claim 82, wherein the agent is selected from the groupconsisting of arginine derivatives, citrulline derivatives, indazoles,imidazolin-N-oxides, phenylimidazoles, 21-aminosteroids, biphenyls,piperidine derivatives or derivatives of any of the above which are NOSinhibitors or prodrugs thereof.
 84. A method according to claim 1,wherein the agent is an agent which, in the peripheral and/or centralnervous system, is capable of substantially inhibiting the production ofguanylate cyclase or substantially counteracting the action of guanylatecyclase or substantially inhibiting the production of cyclic guanylatemonophosphate (cGMP) or substantially counteracting the action of cyclicguanylate monophosphate (cGMP) or substantially inhibiting any furthersteps in the reaction induced by cyclic guanylate monophosphate (cGMP).85. A method according to claim 34, wherein the agent comprises aguanylate cyclase inhibitor.
 86. A method according to claim 84, whereinthe agent comprises a guanylate cyclase inhibitor.
 87. A methodaccording to claim 86, wherein the agent comprises a quinoxaline orderivatives thereof which are guanylate cyclase inhibitors.
 88. A methodaccording to claim 84, wherein the agent comprises a cGMP inhibitor. 89.A method according to claim 84, wherein the agent comprises capable ofsubstantially counteracting the action of protein kinase C.
 90. A methodaccording to claim 1, wherein the agent is an agent which, in theperipheral and/or central nervous system, is capable of substantiallyinhibiting the production of CGRP or substantially inhibiting therelease of CGRP or substantially counteracting the action of CGRP orsubstantially inhibiting the binding of CGRP to receptors for CGRP. 91.A method according to claim 34, wherein the agent comprises a CORPinhibitor.
 92. A method according to claim 90, wherein the agentcomprises a CGRP inhibitor.
 93. A method according to claim 1, whereinthe agent is an agent which, in the peripheral and/or central nervoussystem, is capable of substantially inhibiting the production ofsubstance P or substantially inhibiting the release of substance P orsubstantially counteracting the action of substance P or substantiallyinhibiting the binding of substance P to receptors for substance P. 94.A method according to claim 1, wherein the agent is an agent which, inthe peripheral and/or central nervous system, is capable ofsubstantially inhibiting the production of neurokinin A or substantiallyinhibiting the release of neurokinin A or substantially counteractingthe action of neurokinin A or substantially inhibiting the binding ofneurokinin A to receptors for neurokinin A.
 95. A method according toclaim 1, wherein the agent is an agent which, in the peripheral and/orcentral nervous system, is capable of substantially inhibiting theproduction of neurokinin B or substantially inhibiting the release ofneurokinin B or substantially counteracting the action of neurokinin Bor substantially inhibiting binding of neurokinin B to receptors forneurokinin B.
 96. A method according to claim 95, wherein the agentcomprises an NK2 receptor antagonist.
 97. A method according to claim96, wherein the agent comprises a peptidomimetic or derivatives thereofwhich are NK2 receptor antagonists or prodrugs thereof.
 98. A methodaccording to claim 1, wherein the agent is an agent which, in theperipheral and/or central nervous system, is capable of substantiallyinhibiting the production of bradykinin or substantially inhibiting therelease of bradykinin or substantially counteracting the action ofbradykinin or substantially inhibiting binding of bradykinin toreceptors for bradykinin.
 99. A method according to claim 34, whereinthe agent comprises a bradykinin antagonist.
 100. A method according toclaim 95, wherein the agent comprises a bradykinin antagonist.
 101. Amethod according to claim 100, wherein the agent comprises apeptidomimetic or derivatives thereof which are bradykinin receptorantagonists or prodrugs thereof.
 102. A method according to claim 1,wherein the agent is an agent which, in the peripheral and/or centralnervous system, is capable of substantially inhibiting the production ofPACAB or substantially inhibiting the release of PACAB or substantiallycounteracting the action of PACAB or substantially inhibiting binding ofPACAB to receptors for PACAB.
 103. A method according to claim 34,wherein the agent comprises a PACAB inhibitor.
 104. A method accordingto claim 102, wherein the agent comprises a PACAB inhibitor.
 105. Amethod according to claim 1, wherein the agent is an agent which, in theperipheral and/or central nervous system, is capable of substantiallyinhibiting the production of adenosine or substantially inhibiting therelease of adenosine or substantially counteracting the action ofadenosine or substantially inhibiting binding of adenosine to adenosineA2 receptors.
 106. A method according to claim 34, wherein the agentcomprises an A receptor antagonist.
 107. A method according to claim105, wherein the agent comprises an A2 receptor antagonist.
 108. Amethod according to claim 107, wherein the agent comprises a xanthinederivative or derivatives thereof which are A2 receptor antagonists orprodrugs thereof.
 109. A method according to claim 1, wherein the agentis an agent which, in the peripheral and/or central nervous system, iscapable of substantially enhancing the production of adenosine orsubstantially enhancing the release of adenosine or substantiallyenhancing the action of adenosine or substantially activating adenosineA1 receptors.
 110. A method according to claim 34, wherein the agentcomprises an adenosine uptake inhibitor.
 111. A method according toclaim 109, wherein the agent comprises an adenosine uptake inhibitor.112. A method according to claim 111, wherein the agent comprises apyrimidine derivative or homopiperazine derivative or derivatives of anyof the above which are adenosine uptake inhibitors or prodrugs thereof.113. A method according to claim 34, wherein the agent comprises an A1receptor agonist.
 114. A method according to claim 109, wherein theagent comprises an A1 receptor agonist.
 115. A method according to claim114, wherein the agent is selected from the group consisting ofadenosine derivatives, adeninglucosides or derivatives thereof which areA1 receptor agonists or prodrugs thereof.
 116. A method according toclaim 1, wherein the agent is an agent which, in the peripheral-and/orcentral nervous system, is capable of substantially enhancing theproduction of galanine or substantially enhancing the release ofgalanine or substantially enhancing the action of galanine orsubstantially activating receptors for galanine.
 117. A method accordingto claim 34, wherein the agent comprises a galanine receptor agonist.118. A method according to claim 116, wherein the agent comprises agalanine receptor agonist.
 119. A method according to claim 1, whereinthe agent is an agent which, in the peripheral and/or central nervoussystem, is capable of substantially enhancing the production ofnorepinephrine or substantially enhancing the release of norepinephrineor substantially enhancing the action of norepinephrine or substantiallyactivating receptors for norepinephrine.
 120. A method according toclaim 34, wherein the agent comprises an norepinephrine receptoragonist.
 121. A method according to claim 119, wherein the agentcomprises an norepinephrine receptor agonist.
 122. A method according toclaim 121, wherein the agent comprises an a-2 receptor agonist.
 123. Amethod according to claim 122, wherein the agent is selected from thegroup consisting of aminoimidazolines, thiazinamines, imidazoles, orderivatives of any of the above which are a-2 receptor agonists orprodrugs thereof.
 124. A method according to claim 1, wherein the agentis an agent which, in the peripheral and/or central nervous system, iscapable of substantially inhibiting the production of glycine orsubstantially inhibiting the release of glycine or substantiallycounteracting the action of glycine or substantially inhibiting bindingof glycine to receptors for glycine.
 125. A method according to claim34, wherein the agent comprises a glycine antagonist.
 126. A methodaccording to claim 124, wherein the agent comprises a glycineantagonist.
 127. A method according to claim 126, wherein the agent isselected from the group consisting of aminopyrrolidinones, kynurenicacid derivatives, tetrahydroquinolines, kynurenic acid derivatives,indoles, glycine derivatives, quinoxalinediones, dicarbamates orderivatives of any of the above which are glycine antagonists orprodrugs thereof.
 128. A method according to claim 1, wherein the agentis an agent which, in the peripheral and/or central nervous system, iscapable of substantially inhibiting the production of histamin orsubstantially inhibiting the release of histamin or substantiallycounteracting the action of histamin or substantially inhibiting bindingof histamine to receptors for histamin.
 129. A method according to claim1, wherein the agent is a agent which, in the peripheral and/or centralnervous system, is capable of substantially inhibiting the production ofneurotrophins or substantially inhibiting the release of neurotrophinsor substantially counteracting the action of neurotrophins orsubstantially inhibiting binding of neurotrophins to receptors forneurotrophins.
 130. A method according to claim 34, wherein the agentcomprises a neurotrophin receptor antagonist.
 131. A method according toclaim 129, wherein the agent comprises a neurotrophin receptorantagonist.
 132. A method according to claim 1, wherein the agent iscapable of substantially inhibiting the action of Na⁺ ion channels inthe peripheral and/or central nervous system.
 133. A method according toclaim 34, wherein the agent comprises a Na⁺ channel blocker.
 134. Amethod according to claim 132, wherein the agent comprises a Na⁺ channelblocker.
 135. A method according to claim 134, wherein the agent isselected from the group consisting of triazines,diphenylmethylpiperazines, hydantoins, aminopiperidines, benzthiazoles,dibenzazepines, phenylamides, aminoethylanisoles or derivatives of anyof the above which are Na⁺ channel blockers or prodrugs thereof.
 136. Amethod according to claim 1, wherein the agent is capable ofsubstantially inhibiting the action of Ca²⁺ ion channels in theperipheral and/or central nervous system.
 137. A method according toclaim 34, wherein the agent comprises a Ca²⁺ channel blocker.
 138. Amethod according to claim 136, wherein the agent is a Ca²⁺ channelblocker.
 139. A method according to claim 138, wherein the agent isselected from the group consisting of diphenylmethylpiperazines,arylphosphonic esters or derivatives of any of the above which are Ca²⁺channel blockers or prodrugs thereof.
 140. A method of treatment oftension-type headache comprising administering to a person in need ofsuch treatment an effective amount of an agent which is capable ofsubstantially inhibiting the action of the enzyme nitric oxide synthase(NOS) and thereby reduces chronic pain in connection with tension-typeheadache.
 141. A method according to claim 140, wherein the agent isselected from the group consisting of arginine derivatives, citrullinederivatives, indazoles, imidazolin-N-oxides, phenylimidazoles,biphenyls, piperidine derivatives or derivatives of any of the abovewhich are NOS inhibitors or prodrugs thereof.
 142. A method of screeninga drug for the ability to alleviate a tension-type headache whichcomprises comparing the relationship of pain intensity to pressureintensity when the trapezoid muscle is palpated at different pressureintensities for (a) persons having tension-type headaches aftertreatment with the drug, and (b) persons having tension-type headaches,treated with a placebo, and determining if the relationship is altered.